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Abstracts

Colorectal Cancer
Updated: 08/26/2004

ABSTRACTS

The growth of carcinogen-induced colon cancer in rats is inhibited by cimetidine.

Adams WJ, Lawson JA, Nicholson SE, et al.

Eur J Surg Oncol. 1993 Aug; 19(4):332-5.

Colon cancer was induced in 40 Sprague Dawley rats using a 10-week course of 1,2 dimethylhydrazine (DMH). Twenty animals received cimetidine in their drinking water, commencing 5 weeks after concluding the course of DMH. After five weeks treatment of the animals were sacrificed and the colon and rectum excised. Tumours were assessed histologically for depth of invasion, inflammatory cell response and stained for Proliferating Cell Nuclear Antigen (PCNA), as a measure of tumour proliferative index. PCNA staining was measured using a computerized image analysis system. There were 25 tumours in the cimetidine treated group and 20 in controls. In the control group, 10% of the tumours were benign, 35% malignant polyps, 40% invading through submucosa and 15% invading through the bowel wall, as opposed to 40%, 44%, 8% and 8%, respectively in the cimetidine group (Chi squared test: P = 0.002). The mean proliferative index for control tumours was 27.9% and for the cimetidine tumours 23.1% t test: P = 0.002). It is concluded that cimetidine inhibits colon cancer cellular proliferation and slows early tumour invasion in this animal model

Cimetidine inhibits in vivo growth of human colon cancer and reverses histamine stimulated in vitro and in vivo growth.

Adams WJ, Lawson JA, Morris DL.

Gut. 1994 Nov; 35(11):1632-6.

The effect of histamine and cimetidine on the growth of four human colon cancer cell lines was studied. Histamine significantly stimulated the uptake of tritiated thymidine in vitro in a dose dependent manner, to a maximum of 120% and 116% of controls for C170 and LIM2412, respectively. This effect was antagonised by cimetidine, but not diphenhydramine. Histamine also stimulated a dose dependent increase in cyclic adenosine monophosphate accumulation in C170 cells, antagonised by cimetidine. When grown as subcutaneous xenografts in Balb/c nu/nu mice, cimetidine had a significant inhibitory effect on the same two cell lines. The final volume of C170 tumours in animals given cimetidine was 44% of controls. This response was dose dependent, plateauing at a cimetidine dose of 50 mg/kg/day. The final volume of LIM2412 tumours in animals given cimetidine was 60% of controls. Histamine administered locally by a mini-osmotic pump stimulated C170 tumour growth to 164% of controls, was antagonised by cimetidine at a dose of 200 mg/kg/day, but not by lower concentrations. Histamine has a trophic effect on at least two colorectal cancer cell lines in vivo and in vitro. As this effect is antagonised by cimetidine, it may be mediated via tumour histamine type 2 receptors

Short-course cimetidine and survival with colorectal cancer.

Adams WJ, Morris DL.

Lancet. 1994 Dec 24; 344(8939-8940):1768-9.

Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac.

Agarwal B, Rao CV, Bhendwal S, et al.

Gastroenterology. 1999 Oct; 117(4):838-47.

BACKGROUND & AIMS: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (HRIs) were found incidentally to reduce new cases of colon cancer in 2 large clinical trials evaluating coronary events, although most patients in both treatment and control group were taking nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are associated with reduced colon cancer incidence, predominantly by increasing apoptosis. We showed previously that lovastatin induces apoptosis in colon cancer cells. In the present study we evaluated the potential of combining lovastatin with sulindac for colon cancer chemoprevention. RESULTS: Lovastatin, 10-30 micromol/L, augmented sulindac-induced apoptosis up to 5-fold in 3 colon cancer cell lines. This was prevented by mevalonate (100 micromol/L) or geranylgeranylpyrophosphate (10 micromol/L) but not farnesylpyrophosphate (100 micromol/L), suggesting inhibition of geranylgeranylation of target protein(s) as the predominant mechanism. In an azoxymethane rat model of chemical-induced carcinogenesis, the total number of colonic aberrant crypt foci per animal (control, 161 +/- 11) and the number of foci with 4+ crypts (control, 40 +/- 4.5) decreased to 142 +/- 14 (NS) and 43 +/- 2.9 (NS), respectively, with 50 ppm lovastatin alone; to 137 +/- 5.4 (P = 0.053) and 36 +/- 2.1 (NS) with 80 ppm sulindac alone; and to 116 +/- 8.1 (P = 0.004) and 28 +/- 3.4 (P = 0.02) when 50 ppm lovastatin and 80 ppm sulindac were combined. CONCLUSIONS: Addition of an HRI such as lovastatin may augment chemopreventive effects of NSAIDs or/and may allow lower, less toxic doses of these drugs to be used

Anticancer potential of curcumin: preclinical and clinical studies 342.

Aggarwal BB, Kumar A, Bharti AC.

Anticancer Res. 2003 Jan; 23(1A):363-98.

Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over the last 50 years has indicated this polyphenol can both prevent and treat cancer. The anticancer potential of curcumin stems from its ability to suppress proliferation of a wide variety of tumor cells, down-regulate transcription factors NF-kappa B, AP-1 and Egr-1; down-regulate the expression of COX2, LOX, NOS, MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules and cyclin D1; down-regulate growth factor receptors (such as EGFR and HER2); and inhibit the activity of c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases. In several systems, curcumin has been described as a potent antioxidant and anti-inflammatory agent. Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis. Pharmacologically, curcumin has been found to be safe. Human clinical trials indicated no dose-limiting toxicity when administered at doses up to 10 g/day. All of these studies suggest that curcumin has enormous potential in the prevention and therapy of cancer. The current review describes in detail the data supporting these studies

Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: a Southwest Oncology Group study.

Ahnen DJ, Feigl P, Quan G, et al.

Cancer Res. 1998 Mar 15; 58(6):1149-58.

We assessed Ki-ras mutations by single-strand conformation polymorphism followed by DNA sequencing, p53 expression by immunohistochemistry, ploidy status, and S-phase fraction in 66 stage II and 163 stage III colon cancer patients enrolled on a randomized trial of surgery followed by observation or adjuvant levamisole or 5-fluorouracil (5FU) plus levamisole (Intergroup Trial 0035) to see whether these factors were independently associated with survival or with differential effects of adjuvant therapy. A Cox proportional hazards survival model was used to describe marker effects and therapy by marker interactions, with adjustment for the clinical covariates affecting survival. A Bonferroni adjustment was used to account for multiple testing. Mutation of the Ki-ras gene was found in 41% of the cancers and was associated with a poor prognosis in stage II but not stage III. In stage II, 7-year survival was 86% versus 58% in those with wild type versus Ki-ras mutations. After adjustment for treatment and clinical variables, the hazard ratio (HR) for death was 4.5; 95% confidence interval (CI), 1.7-12.1 (P = 0.012). p53 overexpression was found in 63% of cancers and was associated with a favorable survival in stage III but not stage II. Seven-year survival in stage III was 56% with p53 overexpression versus 43% with no p53 expression (HR, 2.2; 95% CI, 1.3-3.6; P = 0.012). Aneuploidy was more common in stage III than in stage II (66 versus 47%; P = 0.009) but was not independently related to survival in either group. The proliferative rate was greater in aneuploid than in diploid cancers but was not related to survival. There was no benefit of adjuvant therapy in stage II nor in any of the stage II subgroups defined by mutational status. In stage III, adjuvant therapy with 5FU plus levamisole improved 7-year survival in patients with wild-type Ki-ras (76 versus 44%; HR, 0.4; 95% CI, 0.2-0.8) and in those without p53 overexpression (64 versus 26%; HR, 0.3; 95% CI, 0.1-0.7). Adjuvant therapy did not benefit those with Ki-ras mutations or p53 overexpression. The effects of adjuvant therapy did not differ according to ploidy status or proliferative rate. Ki-ras mutation is a significant risk factor for death in stage II, and the absence of p53 expression is a significant risk factor for death in stage III colon cancer after adjustment for treatment and clinical covariates. Exploratory analyses suggest that patients with stage III colon cancer with wild-type Ki-ras or no p53 expression benefit from adjuvant 5FU plus levamisole, whereas those with Ki-ras mutations or p53 overexpression do not. An independent study will be required to determine whether response to adjuvant therapy in colon cancer depends on mutational status

Frequent somatic mutations of hMSH3 with reference to microsatellite instability in hereditary nonpolyposis colorectal cancers.

Akiyama Y, Tsubouchi N, Yuasa Y.

Biochem Biophys Res Commun. 1997 Jul 18; 236(2):248-52.

hMSH3 is one of the human DNA mismatch repair genes but has not yet been reported to be associated with hereditary nonpolyposis colorectal cancer. Recently, somatic mutation at a polyadenine tract, i.e., (A)8, in hMSH3 was reported in cancers with microsatellite instability (MI). To clarify the tumorigenetic role of hMSH3, we screened for somatic mutations at the hMSH3 (A)8 repeat in 29 tumors from 23 hereditary nonpolyposis colorectal cancer patients. One or two A deletions in the (A)8 repeat were found in 11 (57.9%) of the 19 MI-positive tumors but not in 10 MI-negative ones, indicating secondary mutations after germline mutations of other mismatch repair genes. Moreover, the MI frequency of three or more nucleotide repeats was higher in hMSH3 (A)8-mutated tumor cells than in nonmutated ones (p<0.05). These data suggest that a mutation of a mismatch repair gene enhances the frequency of another mismatch repair gene mutation, such as of hMSH3, resulting in severe MI

Selenium supplementation enhances low selenium levels and stimulates glutathione peroxidase activity in peripheral blood and distal colon mucosa in past and present carriers of colon adenomas.

Al Taie OH, Seufert J, Karvar S, et al.

Nutr Cancer. 2003; 46(2):125-30.

Selenoproteins such as glutathione peroxidases (GPx), thioredoxin reductases (TrxR), and selenoprotein P (SePP) contain molecular selenium in form of selenocysteines within their active center. They are involved in the defense of reactive oxygen species, which otherwise may cause DNA damage and alterations of protein function. Selenium intake has been linked to colon carcinogenesis in epidemiological and interventional studies. In a double-blinded, placebo-controlled trial, we demonstrate that carriers of colon adenomas present with low basal serum levels of selenium and plasma glutathione peroxidase (pGPx) activity before treatment, but both parameters can be normalized by interventional selenium supplementation. GPx activity in colon mucosa was enhanced in the verum group, albeit this had only borderline significance. No change of activity was observed for mucosal TrxR activity on selenium supplementation. In summary, our results confirm the existence of low selenium levels in patients prone to colon adenomas and show that by selenium supplementation this can be normalized. If prospective trials confirm that selenium supplementation reduces colon cancer incidence rates, it may be concluded that selenium supplementation should be recommended for patients at risk

Retinoic acid and 1,25-dihydroxyvitamin D3 inhibit tenascin-C expression in rat glioma C6 cells.

Alvarez-Dolado M, Gonzalez-Sancho JM, Navarro-Yubero C, et al.

J Neurosci Res. 1999 Oct 15; 58(2):293-300.

Tenascin-C (Tn-C) is an extracellular matrix protein with growth-, invasive-, and angiogenesis-promoting activities. Tn-C is upregulated during wound healing, tumorigenesis, and other pathological conditions. Highly malignant gliomas with poor prognosis exhibit high levels of Tn-C expression. Here we demonstrate that Tn-C RNA expression in glioma C6 cells is inhibited in a dose-dependent manner by retinoic acid (RA) and 1,25-dihydroxyvitamin D3 (1,25-D3). No additive or synergistic effects were found. Inhibition is maximum 24 hr after RA or 1,25-D3 treatment, prior to a delayed cytotoxic effect starting at day 4-5 of treatment, and correlates with a reduction in the synthesis of Tn-C protein. Tn-C expression is also inhibited, but to a lesser extent by prostaglandin D2 (PGD2). Furthermore, both RA and 1,25-D3, but not PGD2 abolish the induction of Tn-C by the tumor promoter 12-O-tetradecanoyl phorbol 13-acetate. The inhibition of Tn-C expression might be relevant for the anti-cancer activity of RA and 1,25-D3

Effects of different doses of fish oil on rectal cell proliferation in patients with sporadic colonic adenomas.

Anti M, Armelao F, Marra G, et al.

Gastroenterology. 1994 Dec; 107(6):1709-18.

BACKGROUND/AIMS: Fish oil supplementation can reduce cytokinetic anomalies in the flat rectal mucosa of patients with sporadic colorectal adenoma. This study attempted to identify an optimum dose for fish oil supplementation and evaluate the persistence of its effects during long-term administration. METHODS: In a double-blind study, 60 patients with sporadic adenomas received 2.5, 5.1, or 7.7 g of fish oil per day or placebo for 30 days. [3H]thymidine autoradiographic labeling indices were calculated in flat rectal mucosal biopsy specimens collected before and after supplementation. In a subsequent study, 15 patients with polyps received 2.5 g of fish oil per day. Proliferative parameters, mucosal fatty acids, and mucosal and plasma alpha-tocopherol levels were evaluated before, during, and after 6 months of supplementation. RESULTS: Mean proliferative indices and mucosal arachidonic acid levels decreased significantly (and to similar degrees) in all treated groups, whereas mucosal eicosapentaenoic and docosahexaenoic acid levels increased. Significantly reduced proliferation was observed only in patients with abnormal baseline patterns. These effects persisted during long-term, low-dose treatment. A transient reduction in mucosal (but not plasma) alpha-tocopherol levels was observed after 1 month of treatment. Side effects were insignificant. CONCLUSIONS: Low-dose fish oil supplementation has short-term and long-term normalizing effects on the abnormal rectal proliferation patterns associated with increased colon cancer risk

Curcumin is an in vivo inhibitor of angiogenesis.

Arbiser JL, Klauber N, Rohan R, et al.

Mol Med. 1998 Jun; 4(6):376-83.

BACKGROUND: Curcumin is a small-molecular-weight compound that is isolated from the commonly used spice turmeric. In animal models, curcumin and its derivatives have been shown to inhibit the progression of chemically induced colon and skin cancers. The genetic changes in carcinogenesis in these organs involve different genes, but curcumin is effective in preventing carcinogenesis in both organs. A possible explanation for this finding is that curcumin may inhibit angiogenesis. MATERIALS AND METHODS: Curcumin was tested for its ability to inhibit the proliferation of primary endothelial cells in the presence and absence of basic fibroblast growth factor (bFGF), as well as its ability to inhibit proliferation of an immortalized endothelial cell line. Curcumin and its derivatives were subsequently tested for their ability to inhibit bFGF-induced corneal neovascularization in the mouse cornea. Finally, curcumin was tested for its ability to inhibit phorbol ester-stimulated vascular endothelial growth factor (VEGF) mRNA production. RESULTS: Curcumin effectively inhibited endothelial cell proliferation in a dose-dependent manner. Curcumin and its derivatives demonstrated significant inhibition of bFGF-mediated corneal neovascularization in the mouse. Curcumin had no effect on phorbol ester-stimulated VEGF production. CONCLUSIONS: These results indicate that curcumin has direct antiangiogenic activity in vitro and in vivo. The activity of curcumin in inhibiting carcinogenesis in diverse organs such as the skin and colon may be mediated in part through angiogenesis inhibition

Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices.

Armstrong B, Doll R.

Int J Cancer. 1975 Apr 15; 15(4):617-31.

Incidence rates for 27 cancers in 23 countries and mortality rates for 14 cancers in 32 countries have been correlated with a wide range of dietary and other variables. Dietary variables were strongly correlated with several types of cancer, particularly meat consumption with cancer of the colon and fat consumption with cancers of the breast and corpus uteri. The data suggest a possible role for dietary factors in modifying the development of cancer at a number of other sites. The usefulness and limitations of the method are discussed

Mortality in patients with familial adenomatous polyposis.

Arvanitis ML, Jagelman DG, Fazio VW, et al.

Dis Colon Rectum. 1990 Aug; 33(8):639-42.

The authors identified 132 patients who died with a documented diagnosis of familial adenomatous polyposis (FAP). A review of the medical records, autopsy reports, and in-depth discussion with local physicians and well-informed family members was performed. It was impossible, even after the review, to ascertain the exact cause of death in 22 patients. In the remaining patients, the cause of death was as follows: metastatic colorectal carcinoma, 64 patients (58.2 percent), (colon, 49 [44.5 percent], rectal, 15 [13.6 percent]); desmoid tumors, 12 (10.9 percent); periampullary carcinoma, 9 (8.2 percent); brain tumors, 8 (7.3 percent); perioperative mortalities, 5 (4.5 percent); adrenal carcinoma, 1 (0.9 percent); and abdominal carcinomatosis, 1 (0.9 percent). Ten patients died of causes not related to FAP. The major causes of death in 36 patients who underwent prophylactic colectomy were desmoid tumor and periampullary malignancy. This finding underscores the importance of lifelong surveillance and periodic endoscopic evaluation in patients with FAP

Ingestion of green tea rapidly decreases prostaglandin E2 levels in rectal mucosa in humans.

August DA, Landau J, Caputo D, et al.

Cancer Epidemiol Biomarkers Prev. 1999 Aug; 8(8):709-13.

The objective of this Phase I/II study was to assess the potential for green tea to be used as a colorectal cancer chemopreventive agent. This study measured the dose-related biological effects of administration of a single dose of green tea on the rectal mucosa of normal volunteers. Volunteers were admitted to the Robert Wood Johnson Medical School Clinical Research Center for 24 h. Baseline blood and rectal biopsy samples were obtained before the volunteers drank 0.6, 1.2, or 1.8 g of green tea solids dissolved in warm water. Blood samples were taken 2, 4, 8, and 24 h after the tea administration. Rectal biopsies were obtained at 4, 8, and 24 h. Prostaglandin E2 (PGE2) levels were analyzed by ELISA. Tea polyphenol levels in the blood, urine, and rectal tissue were measured by high-performance liquid chromatography using a Coulochem electrode array detection system. Statistical comparisons were made using ANOVA. Decreased levels of PGE2 in rectal mucosa were observed at 4 and 8 h after consumption of green tea. There was no correlation between inhibition of PGE2 and tissue or plasma levels of tea polyphenols. Ten of 14 subjects demonstrated a response to green tea, as evidenced by at least a 50% inhibition of PGE2 levels at 4 h. We conclude that green tea constituents have biological activity in inhibiting PGE2 synthesis. Given the 71% "response rate," we believe these data support the study of green tea as a colorectal chemopreventive agent in more long-term Phase II trials

Human ornithine decarboxylase-overproducing NIH3T3 cells induce rapidly growing, highly vascularized tumors in nude mice.

Auvinen M, Laine A, Paasinen-Sohns A, et al.

Cancer Res. 1997 Jul 15; 57(14):3016-25.

Overexpression of human ornithine decarboxylase (ODC) under the control of strong promoters induces morphological transformation of immortalized NIH3T3 and Rat-1 fibroblasts [M. Auvinen et al., Nature (Lond.), 360: 355-358, 1992]. We demonstrate here that ODC-overproducing NIH3T3 cells are tumorigenic in nude mice, giving rise to rapidly growing, large fibrosarcomas at the site of inoculation. The tumors are capable of invading host fat and muscle tissues and are vascularized abundantly. To disclose the molecular mechanism(s) driving the tumorigenic, invasive, and angiogenic phenotype of the tumors, the ODC-overproducing cell lines and tumor tissues were analyzed for the expression of various potential regulators and mediators of cell proliferation, matrix degradation, and angiogenesis. The tumorigenicity of ODC transformants was associated with elevated polyamine levels and down-regulated growth factor receptors. The invasiveness of the ODC-induced tumors could not be attributed to overexpression of various known extracellular matrix-degrading proteases or matrix metalloproteinases. The induction of the tumor neovascularization proved not to be elicited by vascular endothelial growth factor or basic fibroblast growth factor. Instead, the ODC-overexpressing cells appeared to secrete a novel angiogenic factor(s) that was able to promote migration of bovine capillary endothelial cells in collagen gels and increase the proliferation of human endothelial cells in vitro. In parallel, ODC-transformed cells displayed down-regulation of thrombospondin-1 and -2, the negative regulators of angiogenesis. Thus, the induction of the angiogenic phenotype of the ODC transformants is likely due both to increased expression and secretion of the new angiogenesis-stimulating factor(s) and decreased production and release of the antiangiogenic thrombospondins

Cancer chemoprevention by resveratrol: in vitro and in vivo studies and the underlying mechanisms (review).

Aziz MH, Kumar R, Ahmad N.

Int J Oncol. 2003 Jul; 23(1):17-28.

Cancer, next only to heart diseases, is the second leading cause of deaths in the United States of America and many other nations in the world. The prognosis for a patient with metastatic carcinoma of the lung, colon, breast, or prostate (four of the most common and lethal forms of cancer, which together account for more than half of all deaths from cancer in the USA), remains dismal. Conventional therapeutic and surgical approaches have not been able to control the incidence of most of the cancer types. Therefore, there is an urgent need to develop mechanism-based approaches for the management of cancer. Chemoprevention via non-toxic agents could be one such approach. Many naturally occurring agents have shown cancer chemopreventive potential in a variety of bioassay systems and animal models, having relevance to human disease. It is appreciated that an effective and acceptable chemopreventive agent should have certain properties: (a), little or no toxic effects in normal and healthy cells; (b), high efficacy against multiple sites; (c), capability of oral consumption; (d), known mechanism of action; (e), low cost; and (f), acceptance by human population. Resveratrol is one such agent. A naturally occurring polyphenolic antioxidant compound present in grapes, berries, peanuts and red wine. In some bioassay systems resveratrol has been shown to afford protection against several cancer types. The mechanisms of resveratrol's broad cancer chemopreventive effects are not completely understood. In this review, we present the cancer chemopreventive effects of resveratrol in an organ-specific manner. The mechanisms of the antiproliferative/cancer chemopreventive effects of resveratrol are also presented. We believe that continued efforts are needed, especially well-designed pre-clinical studies in the animal models that closely mimic/represent human disease, to establish the usefulness of resveratrol as cancer chemopreventive agent. This should be followed by human clinical trials in appropriate cancer types in suitable populations

Perioperative cimetidine application modulates natural killer cells in patients with colorectal cancer: a randomized clinical study.

Bai D, Yang G, Yuan H, et al.

J Tongji Med Univ. 1999; 19(4):300-3.

Thirty-eight colorectal cancer patients were randomly assigned to treatment group, which took cimetidine in the perioperative period, and control group to which no drug was given. Twenty healthy volunteers served as normal controls. NK cells were measured by immunocytochemical technique. The results showed that NK percentages before treatment in both groups of patients were significantly lower than those in normal controls (P < 0.05). NK cell percentages at admission, before operation, on the 2nd and the 10th postoperative days were 14.84 +/- 4.41, 15.74 +/- 3.75, 17.21 +/- 3.69, 21.05 +/- 4.54, respectively, for the treatment group, and 15.00 +/- 2.77, 13.05 +/- 2.46, 14.21 +/- 2.19, 15.58 +/- 1.68, respectively, for control group. The difference was statistically significant (P < 0.01), suggesting that the perioperative administration of cimetidine could help restore NK cells in colorectal cancer patients

Suppression of human colorectal carcinoma cell growth by wild-type p53.

Baker SJ, Markowitz S, Fearon ER, et al.

Science. 1990 Aug 24; 249(4971):912-5.

Mutations of the p53 gene occur commonly in colorectal carcinomas and the wild-type p53 allele is often concomitantly deleted. These findings suggest that the wild-type gene may act as a suppressor of colorectal carcinoma cell growth. To test this hypothesis, wild-type or mutant human p53 genes were transfected into human colorectal carcinoma cell lines. Cells transfected with the wild-type gene formed colonies five- to tenfold less efficiently than those transfected with a mutant p53 gene. In those colonies that did form after wild-type gene transfection, the p53 sequences were found to be deleted or rearranged, or both, and no exogenous p53 messenger RNA expression was observed. In contrast, transfection with the wild-type gene had no apparent effect on the growth of epithelial cells derived from a benign colorectal tumor that had only wild-type p53 alleles. Immunocytochemical techniques demonstrated that carcinoma cells expressing the wild-type gene did not progress through the cell cycle, as evidenced by their failure to incorporate thymidine into DNA. These studies show that the wild-type gene can specifically suppress the growth of human colorectal carcinoma cells in vitro and that an in vivo-derived mutation resulting in a single conservative amino acid substitution in the p53 gene product abrogates this suppressive ability

Tolerance and incorporation of a high-dose eicosapentaenoic acid diester emulsion by patients with pancreatic cancer cachexia.

Barber MD, Fearon KC.

Lipids. 2001 Apr; 36(4):347-51.

Chemotherapy and radiotherapy offer little benefit to patients with advanced pancreatic cancer. Eicosapentaenoic acid (EPA) has anticancer effects both in vitro and in animal models. The dose of EPA that can be administered to cancer patients has previously been limited by the low purity of available preparations and the tolerability of large capsules. A high-purity preparation of EPA as a 20% oil-in-water diester emulsion allowed a small study of the tolerance, incorporation, and effects of EPA in high doses in five patients with advanced pancreatic cancer. Patients underwent assessment at baseline and every 4 wk thereafter. All patients managed to tolerate a dose providing 18 g EPA per day, with doses between 9 and 27 g daily being taken for at least a month. Dosage was limited by a sensation of fullness, cramping abdominal pain, steatorrhea, and nausea. All such symptoms were controlled by dose reduction or pancreatic enzyme supplements. No other adverse effects attributable to the trial agent were observed. Plasma phospholipid EPA content increased from around 1% at baseline to 10% at 4 wk and 20% at 8 wk. Incorporation of EPA into red blood cell phospholipids reached levels of around 10%. The present study has shown that a novel, high-purity, EPA diester emulsion can be tolerated at a dose providing around 18 g EPA per day with side-effects being easily controlled. The acceptibility of large doses of oral EPA should allow larger controlled clinical studies into potential anticancer effects of EPA

Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group 710.

Baron JA, Beach M, Mandel JS, et al.

1999; 340(2):101-7.

BACKGROUND AND METHODS: Laboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period. RESULTS: The subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95 percent confidence interval, 0.74 to 0.98; P=0.03). The main analysis was based on the 832 subjects (409 in the calcium group and 423 in the placebo group) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group (31 percent) and 159 subjects in the placebo group (38 percent); the adjusted risk ratio was 0.81 (95 percent confidence interval, 0.67 to 0.99; P=0.04). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95 percent confidence interval, 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake. CONCLUSIONS: Calcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas

Involvement of histamine in growth of mouse and rat tumors: antitumoral properties of monofluoromethylhistidine, an enzyme-activated irreversible inhibitor of histidine decarboxylase.

Bartholeyns J, Bouclier M.

Cancer Res. 1984 Feb; 44(2):639-45.

The present study suggests that newly synthesized histamine is involved in the development of some animal tumors (e.g., Lewis lung carcinoma in mice and Morris hepatoma in rats). A marked induction of histidine decarboxylase (HDC) and an increase in the histamine concentration were observed in the tumors approximately 1 week after inoculation, and there were parallel increases in ornithine decarboxylase activity and the concentrations of polyamines. The H2 receptor antagonist, cimetidine, significantly reduced tumor growth in the animal models while the H1 receptor antagonist, dexchlorpheniramine, had no effect, suggesting that histamine could act via H2 receptor sites. Extensive depletion of tumor histamine induced by local injection of Compound 48/80 did not result in a significant cytostatic effect. Monofluoromethylhistidine (MFMH), an enzyme-activated irreversible inhibitor of HDC, retarded the growth of hepatoma tissue culture cells grown in culture, and when infused s.c. at 60 mg/kg/day it greatly inhibited the development of tumors induced i.m. by hepatoma tissue culture cells in Buffalo rats. MFMH also had pronounced antitumoral effects on EMT6 sarcomas and Lewis lung carcinomas in mice, which were associated with inhibition of HDC and depletion of the histamine content of the tumors. These cytostatic effects were clearly enhanced when MFMH was combined in therapy with the specific ornithine decarboxylase inhibitor, DL-alpha-difluoromethylornithine. The antitumoral effects of the combination were associated with marked decreases in the tumor histamine and putrescine contents. It is proposed that nascent histamine, like newly synthesized putrescine and spermidine, plays a role in the rapid proliferation of animal tumors. Inhibition of HDC by essentially nontoxic drugs such as MFMH could represent a novel approach to the control of neoplastic growth

Missing anti-proliferative effect of fish oil on rectal epithelium in healthy volunteers consuming a high-fat diet: potential role of the n-3:n-6 fatty acid ratio.

Bartram HP, Gostner A, Reddy BS, et al.

Eur J Cancer Prev. 1995 Jun; 4(3):231-7.

Several studies have indicated dietary fish oil (FO) as a protective agent in colon carcinogenesis. Rectal cell proliferation as an intermediate biomarker of cancer risk was shown to be reduced by dietary FO in patients with adenomatous polyps and healthy subjects consuming a low-fat diet. Because the synthesis of prostaglandins (PG) which seem to be involved in this process is dependent on the ratio of n-3:n-6 fatty acids in the diet, the present study was designed to investigate whether this FO effect is also detectable in volunteers eating a high-fat diet (50% of energy) with a low n-3:n-6 ratio of 0.25. Twelve healthy volunteers received in addition to a controlled basal diet either FO (4.4 g n-3 fatty acids/day) or corn oil supplements (double-blind, crossover) for two 4-week periods. No significant differences between the two study periods were found for rectal cell proliferation as assessed by bromodeoxyuridine immunohistochemistry and ornithine decarboxylase activity, as well as for mucosal PGE2 release and mucosal membrane fatty acid composition. The results emphasize the importance of dietary n-3:n-6 ratio in determining the effects of FO on rectal cell proliferation

Interleukin-6 blood level is associated with circulating carcinoembryonic antigen and prognosis in patients with colorectal cancer.

Belluco C, Nitti D, Frantz M, et al.

Ann Surg Oncol. 2000 Mar; 7(2):133-8.

BACKGROUND: Interleukin-6 (IL-6) is an important proinflammatory cytokine that has multiple effects on stimulating inflammation and cell growth. Experimental data suggest that carcinoembryonic antigen (CEA) induces the systemic production of IL-6 and that IL-6 may stimulate tumor cell growth at metastatic sites. We tested the hypothesis that blood concentrations of IL-6 are associated with the amount of circulating CEA and with prognosis in patients with colorectal cancer. METHODS: CEA and IL-6 concentrations were measured by using enzyme immunoassay in preoperative serum samples from 208 patients with stages I through IV colorectal cancer. RESULTS: Linear regression analysis showed a significant association between serum values of CEA and IL-6 (r = .544; R2 = .296; P < .001). Patients with stage III and stage IV disease had a significantly higher IL-6 serum concentration than those with stage I and stage II disease. In patients with stages I through III, 5-year survival was 83% in cases with concentrations of IL-6 at 10 pg/ml or less (n = 94) and 56% in cases with IL-6 concentrations of more than 10 pg/ml (n = 54; P = .001; median follow-up time, 46 months). By using multivariate analysis, an IL-6 concentration of more than 10 pg/ml was an independent prognostic factor of survival (relative risk = 1.820; P = .020). CONCLUSIONS: In patients with colorectal cancer, blood concentration of IL-6 is associated with high circulating CEA and advanced stage. Furthermore, an IL-6 concentration of more than 10 pg/ml is an independent negative prognostic marker of survival

Green tea constituent (--)-epigallocatechin-3-gallate inhibits topoisomerase I activity in human colon carcinoma cells.

Berger SJ, Gupta S, Belfi CA, et al.

Biochem Biophys Res Commun. 2001 Oct 19; 288(1):101-5.

DNA topoisomerases I and II are essential for cell survival and play critical roles in DNA metabolism and structure. Inhibitors of topoisomerase constitute a novel family of antitumor agents with demonstrated clinical activity in human malignancies. The clinical use of these agents is limited due to severe toxic effects on normal cells. Therefore, there is a need to develop novel, nontoxic topoisomerase inhibitors that have the ability to spare normal cells. Recent studies have shown that green tea and its major polyphenolic constituent, epigallocatechin-3-gallate (EGCG), impart growth inhibitory responses to cancer cells but not to normal cells. Based on the knowledge that EGCG induces DNA damage, cell cycle arrest, and apoptosis, we considered the possibility of the involvement of topoisomerase in the antiproliferative response of EGCG. Here, for the first time, we show that EGCG inhibits topoisomerase I, but not topoisomerase II in several human colon carcinoma cell lines. Based on this study it is tempting to suggest that combination of EGCG with other conventional topoisomerase inhibitors could be an improved strategy for treatment of colon cancer. The possible role of EGCG as a chemotherapeutic agent needs to be investigated

Cellular thioredoxin reductase activity is regulated by selenium.

Berggren M, Gallegos A, Gasdaska J, et al.

Anticancer Res. 1997 Sep; 17(5A):3377-80.

Selenium (Se) is an essential trace element and has been reported to decrease the incidence of some human cancers. We have investigated the effects of Se on thioredoxin reductase, a selenocysteine containing flavoenzyme, in HT-29 human colon cancer cells grown in serum-free medium. Sodium selenite and other Se containing compounds produced a time and concentration dependent increase in intracellular thioredoxin reductase activity and protein levels. Selenite was the most active of the Se compounds examined: 1 microM selenite produced a 28-fold increase in thioredoxin reductase activity by 1 day and 10 microM selenite over a 60-fold increase by 5 days. The activity of a related non-selenocysteine containing flavoenzyme glutathione reductase was not increased by selenite. Selenite, but not the other Se containing compounds inhibited cell growth at concentrations above 2 microM. The results show that Se can produce large increases in cell thioredoxin reductase activity

Folic acid supplementation and cell kinetics of rectal mucosa in patients with ulcerative colitis.

Biasco G, Zannoni U, Paganelli GM, et al.

Cancer Epidemiol Biomarkers Prev. 1997 Jun; 6(6):469-71.

It has been suggested that colon cancer risk in ulcerative colitis (UC) is correlated to a reduced bioavailability of folate. We studied the effects of folate supplementation on the pattern of rectal cell proliferation in patients affected by long-standing UC. In the rectal mucosa of these patients, an expansion of proliferating cells to the crypt surface is found frequently. This abnormality is considered an intermediate biomarker in chemoprevention trials. Twenty-four patients (13 males; age, 26-70 years; UC duration, 7-34 years) with UC in remission for 1 month at least were assigned randomly to one of the following treatments: (a) folinic acid (15 mg/day) or (b) placebo. Cell proliferation was analyzed through immunohistochemistry on sections of rectal biopsies incubated for 1 hour in a culture medium containing bromodeoxyuridine. Fragments were taken at admission to the study and after 3 months of treatment. As compared to the baseline values, after 3 months of therapy in patients treated with folinic acid, a significant reduction of the frequency of occurrence of labeled cells in the upper 40% of the crypts (phi h value) was observed (0.1836 +/- 0.0278 versus 0.1023 +/- 0.0255; P < 0.01). On the contrary, no significant proliferative changes were observed in the placebo group. These results suggest that folate supplementation contributes to regulating rectal cell proliferation in patients with long-standing UC. These findings may be significant for chemoprevention of colon cancer in these patients

The dietary pigment curcumin reduces endothelial tissue factor gene expression by inhibiting binding of AP-1 to the DNA and activation of NF-kappa B.

Bierhaus A, Zhang Y, Quehenberger P, et al.

Thromb Haemost. 1997 Apr; 77(4):772-82.

The natural occurring pigment curcumin, a major component of the spice turmeric, has been described to have antioxidative, anti-tumorpromoting, anti-thrombotic and anti-inflammatory properties. It appears, that the pleiotropic effects of curcumin are at least partly due to inhibition of the transcription factors NF-kappa B and AP-1. This study investigates the effect of curcumin on the TNF alpha induced expression of endothelial Tissue Factor (TF), the central mediator of coagulation known to be controlled by AP-1 and NF-kappa B. When bovine aortic endothelial cells (BAEC) were preincubated in the presence of curcumin, TNF alpha induced TF gene transcription and expression were reduced. Transient transfection studies with TF-promoter plasmids revealed that both, NF-kappa B and AP-1 dependent TF expression, were reduced by curcumin action. The observed inhibitions were due to distinct mechanisms. Curcumin inhibited TNF alpha induced I kappa B alpha degradation and the nuclear import of NF-kappa B. In contrast, inhibition of AP-1 was due to a direct interaction of curcumin with AP-1-binding to its DNA binding motif. Thus, curcumin inhibits NF-kappa B and AP-1 by two different mechanisms and reduces expression of endothelial genes controlled by both transcription factors in vitro

Does increased endogenous formation of N-nitroso compounds in the human colon explain the association between red meat and colon cancer?

Bingham SA, Pignatelli B, Pollock JR, et al.

Carcinogenesis. 1996 Mar; 17(3):515-23.

High red meat diets have been linked with risk of sporadic colorectal cancer; but their effects on mutations which occur in this cancer are unknown. G-->A transitions in K-ras occur in colorectal cancer and are characteristic of the effects of alkylating agents such as N-nitroso compounds (NOC). We studied th effect of red meat consumption on faecal NOC levels in eight male volunteers who consumed diets low or high in meat (60 or 600 g/day), as beef, lamb or pork, whilst living in a metabolic suite. Increased intake of red meat induced a significant (P<0.024) 3-fold increase from 40 + or - 7 to ab average of 113 + or - 25 microgram/day NOC, a range of exposure in faeces similar to that from tobacco-specific NOC in cigarette smoke. THe diets were isoenergetic and contained equal amounts of fat, but concentrations of heterocyclic amines were low. Faecal excretion of the promotor ammonia was significantly increased to 6.5 + or - 1.08 mmol/day. When the high red meat diets were supplemented with 20 g phytate-free wheat bran in six volunteers there was no reduction in NOC levels (mean 138 + or - 41 microgram/day NOC), but faecal weight increased. Higher starch and non-starch polysaccharide intakes reduced intraluminal cross-linking in microcapsules (r=-0.77) and reduced faecal pH (r=-0.64). In two volunteers there was no effect of 600 g white meat and fish o faecal NOC (mean low white meat diet 68 + or - 10 microgram/day, high white meat 56 + or -6 microgram/day nor on faecal nitrate, nitrite and iron. Faecal nitrite levels increased on changing from a white to red meat diet (mean high white meat diet 46 + or - 7 mg/day, high red meat diet mean 80 + or - 7 mg/day.) Increased endogenous production of NOC and precursors from increased red meat, but not white meat and fish, consumption may be relevant to the aetiology of colorectal cancer

Plasma ferritin, iron intake, and the risk of colorectal polyps.

Bird CL, Witte JS, Swendseid ME, et al.

Am J Epidemiol. 1996 Jul 1; 144(1):34-41.

High iron exposure has been associated with colorectal neoplasia in several studies. The authors investigated plasma ferritin, an indicator of iron stores, and iron intake as risk factors for adenomatous polyps, intermediate markers for colorectal cancer. During 1991-1993, they collected fasting blood samples from and administered questionnaires to men and women 50-75 years old who visited free sigmoidoscopy clinics at a health maintenance organization. Data from 965 subjects (467 cases, 498 controls) were analyzed. Compared with those who had low-normal plasma ferritin concentrations (73-141 micrograms/liter), those with elevated concentrations ( > 289 micrograms/liter) had a multivariate-adjusted odds ratio of 1.5 (95% confidence interval (CI) 1.0-2.3) after excluding subjects with possible non-iron-related elevations in ferritin. Compared with subjects consuming an adequate amount of iron (11.6-13.6 mg/day), multivariate-adjusted odds ratios were 1.6 (95% CI 1.1-2.4) for < 11.6 mg/day and 1.4 (95% CI 0.9-2.0) for > 27.3 mg/day. These results provide further support for a weak positive association between iron exposure and colorectal polyps

Serum lipids and adenomas of the left colon and rectum.

Bird CL, Ingles SA, Frankl HD, et al.

Cancer Epidemiol Biomarkers Prev. 1996 Aug; 5(8):607-12.

Levels of serum lipids are partially determined by several established risk factors for colorectal cancer and are themselves potential risk factors for the disease. However, evaluating serum lipids as risk factors has proved problematic because metabolic events associated with malignant transformation or progression appear to alter serum lipid concentrations. Serum lipid concentrations are less likely to have altered in individuals with precancerous lesions, such as colorectal adenomas. During 1991-1993, we collected fasting blood samples from and provided questionnaires to men and women 50-75 years old, who visited sigmoidoscopy clinics at a health maintenance organization. Serum lipid concentrations from 486 cases with adenomas and 520 controls were analyzed. Compared to subjects in the lowest quintile of serum triglyceride concentrations, subjects in the highest quintile had an adjusted odds ratio of 1.5 (95% confidence interval, 1.0-2.2). The corresponding odds ratio for total cholesterol was 1.3 (0.9-1.9); for high-density lipoprotein cholesterol, it was 1.1 (0.7-1.6); and for low-density lipoprotein cholesterol, it was 1.1 (0.7-1.6). Further adjustment for potential confounding did not alter these results substantively, although determinants of serum triglycerides and high-density lipoprotein cholesterol (e.g., obesity, physical activity, and refined carbohydrate and alcohol intake) in this and other studies may not be sufficiently well measured to avoid residual confounding. Higher levels of serum triglycerides are associated with an increased risk of adenomatous polyps. Consistent with previous studies, serum cholesterol was not inversely related to the risk of colorectal polyps

Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence.

Block G, Patterson B, Subar A.

Nutr Cancer. 1992; 18(1):1-29.

Approximately 200 studies that examined the relationship between fruit and vegetable intake and cancers of the lung, colon, breast, cervix, esophagus, oral cavity, stomach, bladder, pancreas, and ovary are reviewed. A statistically significant protective effect of fruit and vegetable consumption was found in 128 of 156 dietary studies in which results were expressed in terms of relative risk. For most cancer sites, persons with low fruit and vegetable intake (at least the lower one-fourth of the population) experience about twice the risk of cancer compared with those with high intake, even after control for potentially confounding factors. For lung cancer, significant protection was found in 24 of 25 studies after control for smoking in most instances. Fruits, in particular, were significantly protective in cancers of the esophagus, oral cavity, and larynx, for which 28 of 29 studies were significant. Strong evidence of a protective effect of fruit and vegetable consumption was seen in cancers of the pancreas and stomach (26 of 30 studies), as well as in colorectal and bladder cancers (23 of 38 studies). For cancers of the cervix, ovary, and endometrium, a significant protective effect was shown in 11 of 13 studies, and for breast cancer a protective effect was found to be strong and consistent in a meta analysis. It would appear that major public health benefits could be achieved by substantially increasing consumption of these foods

Modulation of inflammation and cytokine production by dietary (n-3) fatty acids.

Blok WL, Katan MB, van der Meer JW.

J Nutr. 1996 Jun; 126(6):1515-33.

The production of pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor, is pivotal in the response to infection. However, overproduction of these cytokines might be detrimental. It has been suggested that (n-3) fatty acids suppress inflammation and ameliorate the course of infection by decreasing the production of pro-inflammatory cytokines. We here, review these effects. Use of (n-3) fatty acids induced moderate clinical improvements in rheumatoid arthritis, psoriasis and colitis, but not in systemic lupus erythematosus. Data on critically ill burn or postoperative cancer patients are still inconclusive. The (n-3) fatty acids markedly inhibited sterile inflammation in animal studies and improved survival in some experimental infections. T cell responses decreased in healthy volunteers but remained unchanged or increased in certain patient groups. The production of pro-inflammatory cytokines decreased in most human studies. The (n-3) fatty acids increased cytokine production capacity in mice. Differences in cytokine-producing cell types studied may account for these paradoxical responses in humans and mice. Although the increased cytokine production in mice is partly mediated by effects on prostaglandins, mechanisms of action in other species remain to be elucidated. The (n-3) fatty acids may be of moderate benefit in some chronic inflammatory diseases. Their therapeutic value and possible hazards in critically ill patients remain to be established

Family history of colorectal tumours and implications for the adenoma-carcinoma sequence: a case control study.

Boutron MC, Faivre J, Quipourt V, et al.

Gut. 1995 Dec; 37(6):830-4.

Family history of colorectal cancer is a risk factor for sporadic colorectal cancer, but it is not known which step of the adenoma-carcinoma pathway it influences. This case control study investigated the relation between family history of cancer and colorectal adenomas and cancers. Family history of colorectal cancer (FHCRC) was as frequent in small (< 10 mm) adenoma patients (11.7%, n = 154) as in polyp free patients (10.6%, n = 426), whereas it was more frequent in patients with large adenoma(s) (18.8%, n = 208; p < 0.01). Odds ratios for FHCRC were 1.2 (p > 0.10) for small adenomas and 2.1 (p < 0.01) for large adenomas. Family history of other (non-colorectal) cancers (FHOC) was similar in the three groups. Patients with a colorectal cancer (n = 171) had more frequently a family history of cancer, both colorectal (15.8%; p < 0.01) and other cancers (35.7%; p < 0.001) than general population controls (n = 309; FHCRC: 8.1%; FHOC: 21.7%). In a logistic model, both factors were independently related to colorectal cancers (odds ratios: 1.9 (p < 0.05) for FHCRC and 2.1 (p < 0.001) for FHOC). These data suggest that family history of colorectal cancer influences only the growth of adenomas or their malignant transformation. The finding of a further predisposition to any type of cancer needs to be confirmed

Preoperative oral arginine and n-3 fatty acid supplementation improves the immunometabolic host response and outcome after colorectal resection for cancer.

Braga M, Gianotti L, Vignali A, et al.

Surgery. 2002 Nov; 132(5):805-14.

BACKGROUND: Previous trials showed that perioperative immunonutrition improved outcome in patients with gastrointestinal cancer. This study was designed to appraise the impact of the simple preoperative oral arginine and n-3 fatty acids supplementation on immune response, gut oxygenation, and postoperative infections. METHODS: Two hundred patients with colorectal neoplasm were randomized to: (a) oral intake for 5 days before surgery of a formula enriched with arginine and n-3 fatty acids (pre-op group; n = 50); (b) same preoperative treatment prolonged after surgery by jejunal infusion (peri-op group; n = 50); (c) oral intake for 5 days before surgery of a standard isoenergetic, isonitrogenous formula (control group; n = 50); and (d) no supplementation before and after operation (conventional group; n = 50). The immune response was measured by phagocytosis ability of polymorphonuclear cells and delayed hypersensitivity response to skin tests. Gut oxygenation and microperfusion were assessed by polarographic probes and laser Doppler flowmetry, respectively. RESULTS: The 4 groups were comparable for demographics, comorbidity, and surgical variables. The 2 groups receiving immunoutrients (pre-op and peri-op) had a significantly better immune response, gut oxygenation, and microperfusion than the other 2 groups. Intent-to-treat analysis showed an overall infection rate of 12% in pre-op, 10% in peri-op, 32% in control, and 30% in conventional groups (P <.04 pre-op and peri-op vs control and conventional). CONCLUSION: Preoperative oral arginine and n-fatty acids improves the immunometabolic response and decreases the infection rate. Postoperative prolongation with such supplemented formula has no additional benefit

Enhanced cancer growth in mice administered daily human-equivalent doses of some H1-antihistamines: predictive in vitro correlates.

Brandes LJ, Warrington RC, Arron RJ, et al.

J Natl Cancer Inst. 1994 May 18; 86(10):770-5.

BACKGROUND: Present studies of drug-induced tumor growth promotion have evolved from earlier investigations into the mechanism of action of N,N-diethyl-2-[4-(phenylmethyl)phenoxy[ethanamine.HCl, a tamoxifen derivative which potently inhibits lymphocyte mitogenesis in vitro and stimulates tumor growth in vivo. It is thought that potency to bind to intracellular histamine receptors (HIC), some of which are on cytochromes P450, may correlate with tumor growth-promoting activity. PURPOSE: We assessed the effectiveness of five in vitro assays in predicting in vivo tumor growth stimulation by the H1-antihistamines loratadine, astemizole, cetirizine, hydroxyzine, and doxylamine. METHODS: Potency of each agent was ranked 1-5 in each of the following in vitro assays: 1) inhibition of [3H]histamine binding to microsomal HIC, 2) inhibition of histamine binding to microsomal P450, 3) inhibition of the P450-catalyzed demethylation of aminopyrine, 4) inhibition of lymphocyte mitogenesis, and 5) stimulation of tumor colony formation. An overall rank score was assigned to each drug and correlated with tumor growth stimulation in vivo. Two laboratories conducted in vivo studies in a blinded fashion. Female C57BL and C3H mice were given a subcutaneous injection on day 1 of syngeneic B16F10 melanoma cells (5 x 10(5)) or C-3 fibrosarcoma cells (1 x 10(5)), respectively. Mice were randomly assigned to treatment groups, then received a single, daily intraperitoneal injection of an estimated human-equivalent dose (or range of doses) of antihistamine or vehicle control for 18-21 days before being killed. Tumors were surgically removed and wet weights compared statistically among groups. RESULTS: The cumulative potency of each drug in affecting tumor growth or growth mechanisms in the five in vitro assays ranked as follows: Loratidine and astemizole ranked highest and were equally potent, followed in decreasing order by hydroxyzine, doxylamine, and cetirizine. A significant correlation (r = .97; P < .02) was observed between the rank order of potency of the antihistamines in all five in vitro assays and the rank order to enhance tumor growth in vivo: Loratidine and astemizole significantly (P < .001) promoted the growth of both melanoma and fibrosarcoma, hydroxyzine significantly (P < .001) promoted the growth of melanoma, while doxylamine and cetirizine did not promote the growth of either tumor. CONCLUSION: Data demonstrate that the in vitro assays predicted the propensity of each H1-antihistamine to stimulate cancer growth in vivo. IMPLICATION: These in vitro tests may prove valuable to screen potential tumor growth promoters

Relation of serum antioxidant vitamins to the risk of colorectal adenoma.

Breuer-Katschinski B, Nemes K, Marr A, et al.

Digestion. 2001; 63(1):43-8.

The relation between risk of colorectal adenoma and serum concentrations of vitamins A, C, E and carotene was examined in a population-based case-control study of 105 cases of colorectal adenoma and a similar number of hospital controls showing no polyps at colonoscopy and a second control group of population controls. There were no significant associations with serum concentrations of vitamins C and E and carotene. Serum concentrations of vitamin A were significantly inversely related to the risk of colorectal adenoma when cases were compared with both control groups. After adjustment for energy intake, smoking, alcohol, estrogen therapy, body-mass-index and social class the inverse association between vitamin A and colorectal adenoma was even more marked. For the highest versus the lowest quartile of serum levels the adjusted RR was 0.23 (0.07-0.73) in relation to hospital controls and 0.08 (0.02-0.25) in relation to population controls. These findings suggest that the risk of developing colorectal adenomas is reduced in those with high vitamin A levels

[Determination of vascular endothelial growth factor (VEGF) concentration in serum of patients with colorectal carcinoma] 353.

Broll R, Erdmann H, Windhovel U, et al.

Langenbecks Arch Chir Suppl Kongressbd. 1998; 115(Suppl I):315-8.

The aim of our study was to determine the serum concentration of VEGF in 53 patients with a colorectal carcinoma and 22 healthy volunteers (control group) and to compare it with tumor stage and volume. We found significantly higher serum levels in tumor patients in contrast to the control group and between patients with and without distant metastases. There was also a correlation between high serum concentrations and great tumor volumes, but only weak with tumor stage. Our results support the hypothesis that tumor growth is dependent on angiogenesis and that VEGF is a potent growth factor with angiogenic activity

Curcumin, an anti-tumour promoter and anti-inflammatory agent, inhibits induction of nitric oxide synthase in activated macrophages.

Brouet I, Ohshima H.

Biochem Biophys Res Commun. 1995 Jan 17; 206(2):533-40.

L-Arginine-derived nitric oxide (NO) and its derivatives, such as peroxynitrite and nitrogen dioxide, play a role in inflammation and also possibly in the multistage process of carcinogenesis. We investigated the effect of various non-steroidal anti-inflammatory agents and related compounds on the induction of NO synthase (NOS) in RAW 264.7 macrophages activated with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Low concentrations of curcumin, a potent anti-tumour agent having anti-inflammatory and anti-oxidant properties, inhibited NO production, as measured by the amount of nitrite released into the culture medium in 24 h (IC50 = 6 microM). NOS activity in soluble extracts of macrophages activated for 6-24 h in the presence of curcumin (10 microM) was significantly lower than that of macrophages activated without curcumin. Northern-blot and immunoblotting analyses demonstrated that significantly reduced levels of the mRNA and 130-kDa protein of inducible NOS were expressed in macrophages activated with curcumin, compared to those without curcumin. Inhibition of NOS induction was maximal when curcumin was added together with LPS and IFN-gamma and decreased progressively as the interval between curcumin and LPS/IFN-gamma was increased to 18 h

Effect of fish oil on appetite and other symptoms in patients with advanced cancer and anorexia/cachexia: a double-blind, placebo-controlled study.

Bruera E, Strasser F, Palmer JL, et al.

J Clin Oncol. 2003 Jan 1; 21(1):129-34.

PURPOSE: To determine whether high doses of fish oil, administered over 2 weeks, improve symptoms in patients with advanced cancer and decreased weight and appetite. PATIENTS AND METHODS: Sixty patients were randomly assigned to fish oil capsules or placebo. Appetite, tiredness, nausea, well-being, caloric intake, nutritional status, and function were prospectively assessed at days 1 and 14. RESULTS: The baseline weight loss was 16 +/- 11 and 16 +/- 8 kg in the fish oil (n = 30) and placebo (n = 30) group respectively, whereas the baseline appetite (0 mm = best and 10 mm = worst) was 58 +/- 24 mm and 67 +/- 19 mm, respectively (P = not significant). The mean daily dose was 10 +/- 4 (fish oil group) and 9 +/- 3 (placebo group) capsules, which provided 1.8 g of eicosapentaenoic acid and 1.2 g of docosahexaenoic acid in the fish oil group. No significant differences in symptomatic or nutritional parameters were found (P <.05), and there was no correlation between changes in different variables between days 1 and 14 and the fish oil doses. Finally, the majority of the patients were not able to swallow more than 10 fish oil capsules per day, mainly because of burping and aftertaste. CONCLUSION: Fish oil did not significantly influence appetite, tiredness, nausea, well-being, caloric intake, nutritional status, or function after 2 weeks compared with placebo in patients with advanced cancer and loss of both weight and appetite

The effect of high doses of folic acid on the overexpression of ornithine decarboxylase and S-adenosylmethionine content in human colon adenomatous polyps.

Bukin YUV, Draudin-Krylenko VA, Levchuk AA, et al.

Ann N Y Acad Sci. 2001 Dec; 952:175-6.

It was shown that the 3-month supplementation of patients having colon polyps with folic acid (5 mg/day) led to a 35% decrease in abnormally high ornithine decarboxylase activity in polyps that was accompanied by a 43% increase of S-adenosylmethionine content in polyps

Phase I clinical study of fish oil fatty acid capsules for patients with cancer cachexia: cancer and leukemia group B study 9473.

Burns CP, Halabi S, Clamon GH, et al.

Clin Cancer Res. 1999 Dec; 5(12):3942-7.

The purpose of this study was to determine the maximum tolerated dose and dose-limiting toxicities of fish oil fatty acid capsules containing omega-3 fatty acid ethyl esters. Twenty-two patients with neoplastic disease not amenable to curative therapy who had lost 2% of body weight over a previous 1 month time period were given an escalating dose of fish oil fatty acids. The maximum tolerated dose was found to be 0.3 g/kg per day of this preparation. This means that a 70-kg patient can generally tolerate up to 21 1-g capsules/day containing 13.1 g of eicosapentaenoic acid + docosahexaenoic acid, the two major omega-3 fatty acids. Dose-limiting toxicity was gastrointestinal, mainly diarrhea, and a poorly described toxicity designated as "unable to tolerate in esophagus or stomach." A patient with chronic lymphocytic leukemia taking the fish oil provided an unusual opportunity to perform a detailed biochemical study of the effect of fish oil capsules on the lipids of malignant cells at several sequential time points in treatment. Studies of the malignant lymphocytes, serum, and whole blood of this one patient revealed an increase in eicosapentaenoic acid, the major component of the fish oil capsules, during fish oil capsule treatment. This study provides a scientific basis for the selection of omega-3 fatty acid doses for future studies in cancer. The maximum tolerated dose found is considerably higher than anticipated from published studies of many human diseases. The observation of a modification of the lipids of leukemic cells, serum, and blood in a patient with chronic leukemia provides a biochemical basis for a possible effect of fish oil supplements on cancer cachexia and tumor growth

Familial polyposis coli and hepatocellular neoplasms 4.

Bussey HJ.

Hepatology. 1990 Jul; 12(1):175-6.

Development of gamma (gamma)-tocopherol as a colorectal cancer chemopreventive agent.

Campbell S, Stone W, Whaley S, et al.

Crit Rev Oncol Hematol. 2003 Sep; 47(3):249-59.

Nutritional factors play an important role in the prevention and promotion of colorectal cancer. Vitamin E is a generic term that describes a group of lipid-soluble chain-breaking antioxidants that includes tocopherols and tocotrienols. Vitamin E occurs in nature as eight structurally related forms that include four tocopherols and four tocotrienols. Vitamin E is a potent membrane-soluble antioxidant. Antioxidants like vitamin E (tocopherols) may prevent colon cancer through several different cellular and molecular mechanisms. Vitamin E in the American diet is primarily available in plant-oil rich foods such as vegetable oils, seeds and nuts and these foods vary widely in their content of alpha-tocopherol and gamma-tocopherol. Vitamin E may help prevent colon cancer by decreasing the formation of mutagens arising from the oxidation of fecal lipids, by decreasing oxidative stress in the epithelial cells of the colon and by molecular mechanisms that influence cell death, cell cycle and transcriptional events. Most epidemiological, experimental and clinical studies have evaluated the alpha-isoform and not the gamma-isoform of vitamin E. Recent epidemiological, experimental and mechanistic evidence suggests that gamma-tocopherol may be a more potent cancer chemopreventive agent than alpha-tocopherol. The differences in chemical reactivity, metabolism and biological activity may contribute to these differences in the effects of gamma-tocopherol when compared with alpha-tocopherol. The rationale supporting the development of gamma-tocopherol as a colorectal cancer preventive agent is reviewed here

Randomized, double-blinded, placebo-controlled intervention study with supplemental calcium in families with hereditary nonpolyposis colorectal cancer.

Cats A, Kleibeuker JH, Van der MR, et al.

J Natl Cancer Inst. 1995 Apr 19; 87(8):598-603.

BACKGROUND: A high-fat diet has been recognized for some time as a major risk factor for colorectal cancer. It is thought that fat promotes this disease by increasing the levels of fatty and bile acids within the colon. These acids irritate and damage the epithelial cells of the colon. As a result of this cellular destruction, an increase in the rate of cellular proliferation occurs. Oral calcium supplementation has been proposed as a dietary intervention for individuals at high risk of colorectal cancer because of its ability to reduce rectal epithelial cell proliferation through the binding of fatty and bile acids. Placebo-controlled studies, however, have yielded varying results. PURPOSE: We conducted a randomized, double-blinded, placebo-controlled trial to test oral calcium supplementation in patients at high risk of developing hereditary nonpolyposis colorectal cancer. METHODS: Thirty subjects at risk for this cancer, with an increased epithelial cell proliferation along the colon and rectum, were randomly assigned to either a placebo group (n = 15) or a treatment group (n = 15). They received either oral calcium carbonate (CaCO3) supplements (1.5 g) or placebo (cellulose and starch) three times a day during a 12-week period. Colonic biopsy specimens (rectal, sigmoidal, and descending) were obtained prior to and after the intervention trial, during endoscopy, for determination of labeling index (LI) of whole crypts and crypt compartments by 5-bromo-2'-deoxyuridine incorporation and immunohistochemistry. Proportional bile acid compositions in duodenal bile and cytolytic activity of fecal water were also determined. All P values represent two-tailed tests of statistical significance. RESULTS: Statistically significant reductions, comparing before with after intervention, in rectal whole-crypt LI after receiving either calcium supplements (from 10.9% +/- 5.2% [mean +/- SD] to 6.2% +/- 1.5%; P < .02) or placebo (from 11.7% +/- 4.7% to 8.2% +/- 3.1%; P < .05) were observed. In the three bowel segments, no statistically significant differences were observed between the supplemental calcium and placebo groups. A statistically significant reduction in cytolytic activity was determined during calcium supplementation (from 57% +/- 41% to 32% +/- 30%; P < .05), whereas in the placebo group, it did not change (from 42% +/- 41% to 36% +/- 27%; P > .10). CONCLUSIONS: Oral calcium supplementation was shown to cause only a minor nonstatistically significant reduction of epithelial cell proliferation in the rectum, compared with placebo, and to have no effect on the same parameter in the sigmoid and descending colon in first-degree relatives of hereditary nonpolyposis colorectal cancer patients. IMPLICATION: These results cast doubt on the value of calcium supplementation in the prevention of colorectal cancer, especially in individuals already consuming an adequate amount of dietary calcium

Safety and anti-inflammatory activity of curcumin: a component of turmeric (Curcuma longa).

Chainani-Wu N.

J Altern Complement Med. 2003 Feb; 9(1):161-8.

INTRODUCTION: Turmeric is a spice that comes from the root Curcuma longa, a member of the ginger family, Zingaberaceae. In Ayurveda (Indian traditional medicine), turmeric has been used for its medicinal properties for various indications and through different routes of administration, including topically, orally, and by inhalation. Curcuminoids are components of turmeric, which include mainly curcumin (diferuloyl methane), demethoxycurcumin, and bisdemethoxycurcmin. OBJECTIVES: The goal of this systematic review of the literature was to summarize the literature on the safety and anti-inflammatory activity of curcumin. METHODS: A search of the computerized database MEDLINE (1966 to January 2002), a manual search of bibliographies of papers identified through MEDLINE, and an Internet search using multiple search engines for references on this topic was conducted. The PDR for Herbal Medicines, and four textbooks on herbal medicine and their bibliographies were also searched. RESULTS: A large number of studies on curcumin were identified. These included studies on the antioxidant, anti-inflammatory, antiviral, and antifungal properties of curcuminoids. Studies on the toxicity and anti-inflammatory properties of curcumin have included in vitro, animal, and human studies. A phase 1 human trial with 25 subjects using up to 8000 mg of curcumin per day for 3 months found no toxicity from curcumin. Five other human trials using 1125-2500 mg of curcumin per day have also found it to be safe. These human studies have found some evidence of anti-inflammatory activity of curcumin. The laboratory studies have identified a number of different molecules involved in inflammation that are inhibited by curcumin including phospholipase, lipooxygenase, cyclooxygenase 2, leukotrienes, thromboxane, prostaglandins, nitric oxide, collagenase, elastase, hyaluronidase, monocyte chemoattractant protein-1 (MCP-1), interferon-inducible protein, tumor necrosis factor (TNF), and interleukin-12 (IL-12). CONCLUSIONS: Curcumin has been demonstrated to be safe in six human trials and has demonstrated anti-inflammatory activity. It may exert its anti-inflammatory activity by inhibition of a number of different molecules that play a role in inflammation

Cyclooxygenase inhibition and mechanisms of colorectal cancer prevention.

Chan TA.

Curr Cancer Drug Targets. 2003 Dec; 3(6):455-63.

Colorectal cancer is a leading cause of cancer death throughout the world. The high prevalence and mortality associated with colon cancer make effective prevention and treatment an important public health and economic concern. Among the few agents known to inhibit colorectal tumorigenesis are the nonsteroidal anti-inflammatory drugs or NSAIDs, as well as newer agents such as celecoxib and rofecoxib. Both epidemiologic studies and investigations with animals show that these compounds possess marked anti-colorectal cancer properties. NSAIDS are widely known to be inhibitors of the cyclooxygenase (COX) enzymes, and it is thought that the chemopreventive effects of NSAIDs are at least in part due to this ability to inhibit COX. More recent studies, however, have suggested that NSAIDs may also exert anti-cancer effects through mechanisms independent of COX inhibition. COX-dependent and COX-independent mechanisms are not mutually exclusive and it is likely that both are involved in the biological activity of NSAIDs

Chemotherapeutic potential of curcumin for colorectal cancer.

Chauhan DP.

Curr Pharm Des. 2002; 8(19):1695-706.

Colorectal cancer is one of the leading causes of cancer deaths in the Western world. More than 56,000 newly diagnosed colorectal cancer patients die each year in the United States. Available therapies are either not effective or have unwanted side effects. Epidemiological data suggest that dietary manipulations play an important role in the prevention of many human cancers. Curcumin the yellow pigment in turmeric has been widely used for centuries in the Asian countries without any toxic effects. Epidemiological data also suggest that curcumin may be responsible for the lower rate of colorectal cancer in these countries. Curcumin is a naturally occurring powerful anti-inflammatory medicine. The anticancer properties of curcumin have been shown in cultured cells and animal studies. Curcumin inhibits lipooxygenase activity and is a specific inhibitor of cyclooxygenase-2 expression. Curcumin inhibits the initiation of carcinogenesis by inhibiting the cytochrome P-450 enzyme activity and increasing the levels of glutathione-S-transferase. Curcumin inhibits the promotion/progression stages of carcinogenesis. The anti-tumor effect of curcumin has been attributed in part to the arrest of cancer cells in S, G2/M cell cycle phase and induction of apoptosis. Curcumin inhibits the growth of DNA mismatch repair defective colon cancer cells. Therefore, curcumin may have value as a safe chemotherapeutic agent for the treatment of tumors exhibiting DNA mismatch repair deficient and microsatellite instable phenotype. Curcumin should be considered as a safe, non-toxic and easy to use chemotherapeutic agent for colorectal cancers arise in the setting of chromosomal instability as well as microsatellite instability

Epigallocatechin-3-gallate-induced stress signals in HT-29 human colon adenocarcinoma cells.

Chen C, Shen G, Hebbar V, et al.

Carcinogenesis. 2003 Aug; 24(8):1369-78.

Epigallocatechin-3-gallate (EGCG), a major component in green tea polyphenols, has been proven to suppress colonic tumorigenesis in animal models and epidemiological studies. As EGCG is retained in the gastrointestinal tract after oral administration, this pharmacokinetics property gives it the potential to function as a chemopreventive agent against colon cancer. In this study, human colorectal carcinoma HT-29 cells were treated with EGCG to examine the anti-proliferative and pro-apoptotic effects of EGCG, as well as the molecular mechanism underlying these effects. Cell viability assay, nuclear staining, DNA fragmentation, caspase assay, cytochrome c release, DiOC6(3) staining, mitogen-activated protein kinases (MAPK) phosphorylation and trypan blue exclusion assays, were utilized to dissect the signaling pathways induced by EGCG. After 36 h treatment, EGCG inhibited HT-29 cell growth with an IC50 of approximately 100 microM. HT-29 cells treated with doses higher than 100 microM showed apparent nuclear condensation and fragmentation, which was confirmed by DNA laddering. Caspase-3 and -9 activation was detected after 12 h treatment, accompanied by mitochondrial transmembrane potential transition and cytochrome c release. Activation of MAPKs was detected as early signaling event elicited by EGCG. Inhibition of c-Jun N-terminal kinase (JNK) pathway showed the involvement of JNK in EGCG-induced cytochrome c release and cell death. EGCG-induced JNK activation was blocked by the antioxidants glutathione and N-acetyl-l-cysteine, suggesting that the cell death signaling was potentially triggered by oxidative stress. In summary, our results from this study suggest that in HT-29 human colon cancer cells (i) EGCG treatment causes damage to mitochondria, and (ii) JNK mediates EGCG-induced apoptotic cell death

Green tea epigallocatechin gallate shows a pronounced growth inhibitory effect on cancerous cells but not on their normal counterparts.

Chen ZP, Schell JB, Ho CT, et al.

Cancer Lett. 1998 Jul 17; 129(2):173-9.

(-)-Epigallocatechin gallate (EGCG), a catechin polyphenol compound, represents the main ingredient of green tea extract. Although EGCG has been shown to be growth inhibitory in a number of tumor cell lines, it is not clear whether the effect is cancer-specific. In this study we compared the effect of EGCG on the growth of SV40 virally transformed WI38 human fibroblasts (WI38VA) with that of normal WI38 cells. The IC50 value of EGCG was estimated to be 120 and 10 microM for WI38 and WI38VA cells, respectively. Thus, EGCG at 40 microM completely inhibited the growth of WI38VA cells, but had little or no inhibitory effect on the growth of WI38 cells. Similar differential growth inhibition was also observed between a human colorectal cancer cell line (Caco-2), a breast cancer cell line (Hs578T) and their respective normal counterparts. EGCG at a concentration range of 40-200 microM induced a significant amount of apoptosis in WI38VA cultures, but not in WI38 cultures, as determined by terminal deoxynucleotidyl transferase assay. After exposure to EGCG at 200 microM for 8 h, more than 50% of WI38VA cells in a confluent culture became apoptotic. In contrast, less than 1% of WI38 cells displayed apoptotic labeling under the same condition. EGCG did not affect the serum-induced expression of c-fos and c-myc genes in normal WI38 cells. However, it significantly enhanced their expression in transformed W138VA cells. It is possible that differential modulation of certain genes, such as c-fos and c-myc, may cause differential effects of EGCG on the growth and death of cancer cells

Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions.

Cheng AL, Hsu CH, Lin JK, et al.

Anticancer Res. 2001 Jul; 21(4B):2895-900.

Curcumin (diferuloylmethane), a yellow substance from the root of the plant Curcuma longa Linn., has been demonstrated to inhibit carcinogenesis of murine skin, stomach, intestine and liver. However, the toxicology, pharmacokinetics and biologically effective dose of curcumin in humans have not been reported. This prospective phase-I study evaluated these issues of curcumin in patients with one of the following five high-risk conditions: 1) recently resected urinary bladder cancer; 2) arsenic Bowen's disease of the skin; 3) uterine cervical intraepithelial neoplasm (CIN); 4) oral leucoplakia; and 5) intestinal metaplasia of the stomach. Curcumin was taken orally for 3 months. Biopsy of the lesion sites was done immediately before and 3 months after starting curcumin treament. The starting dose was 500 mg/day. If no toxicity > or = grade II was noted in at least 3 successive patients, the dose was then escalated to another level in the order of 1,000, 2,000, 4,000, 8,000, and 12,000 mg/day. The concentration of curcumin in serum and urine was determined by high pressure liquid chromatography (HPLC). A total of 25 patients were enrolled in this study. There was no treatment-related toxicity up to 8,000 mg/day. Beyond 8,000 mg/day, the bulky volume of the drug was unacceptable to the patients. The serum concentration of curcumin usually peaked at 1 to 2 hours after oral intake of crucumin and gradually declined within 12 hours. The average peak serum concentrations after taking 4,000 mg, 6,000 mg and 8,000 mg of curcumin were 0.51 +/- 0.11 microM, 0.63 +/- 0.06 microM and 1.77 +/- 1.87 microM, respectively. Urinary excretion of curcumin was undetectable. One of 4 patients with CIN and 1 of 7 patients with oral leucoplakia proceeded to develop frank malignancies in spite of curcumin treatment. In contrast, histologic improvement of precancerous lesions was seen in 1 out of 2 patients with recently resected bladder cancer, 2 out of 7 patients of oral leucoplakia, 1 out of 6 patients of intestinal metaplasia of the stomach, I out of 4 patients with CIN and 2 out of 6 patients with Bowen's disease. In conclusion, this study demonstrated that curcumin is not toxic to humans up to 8,000 mg/day when taken by mouth for 3 months. Our results also suggest a biologic effect of curcumin in the chemoprevention of cancer

Temporal patterns in colorectal cancer incidence, survival, and mortality from 1950 through 1990.

Chu KC, Tarone RE, Chow WH, et al.

J Natl Cancer Inst. 1994 Jul 6; 86(13):997-1006.

BACKGROUND: Colorectal cancer mortality rates among U.S. white males remained relatively constant from 1950 through 1984 but declined sharply from 1985 through 1990. Those for U.S. white females decreased consistently from 1950 through 1984, with an acceleration of the decline from 1985 through 1990. PURPOSE: A study was planned to investigate patterns in incidence, survival, and mortality rates over time in order to examine possible reasons for the gender difference in mortality trends and for the decrease in the slope of the mortality trends for both males and females in the late 1980s. METHODS: Incidence and survival data from the Connecticut Cancer Registry were examined to investigate the gender differences in mortality rates from 1950 through 1984. Incidence and survival data from the Surveillance, Epidemiology, and End Results (SEER) Program were investigated to examine reasons for the abrupt downturn in mortality rates for both white males and white females beginning around 1985. RESULTS: During the period 1950 through 1984, the colorectal cancer incidence rates in Connecticut increased for males and declined slightly for females. Survival rates were similar for both sexes, increasing on average over 1% per year for both females and males from 1950 through 1984. Examination of SEER data from 1975 through 1990 revealed that for both males and females there were 1) declines in overall incidence and mortality rates beginning in the mid-1980s, 2) steady declines in distant disease incidence rates since 1975, 3) increases in regional disease incidence rates until the early 1980s followed by declines in the late 1980s, and 4) increases in local disease incidence rates until the mid-1980s followed by declines in the late 1980s. Age-period-cohort analyses of mortality rates indicated a statistically significant moderation of colorectal cancer risk with both advancing birth cohorts and recent calendar periods. CONCLUSIONS: The gender differences in colorectal cancer mortality rate trends observed from 1950 through 1984 are due to differences in incidence rate trends between males and females. Declining colorectal mortality rates in the late 1980s for males and females appear to reflect improved early detection. The peaking and subsequent decline of stage-specific incidence rates at later years for successively lower stage indicate sequential stage shifts as cancers are detected increasingly earlier over time. The increased use of sigmoidoscopy and fecal occult blood tests (triggering colonoscopy) appears to have played an important role in reducing colorectal cancer mortality. Improvements in birth cohort trends in risk for colorectal cancer for each sex suggest that lifestyle changes may have also contributed to the steady reductions in colorectal cancer mortality

Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group.

Clark LC, Combs GF, Jr., Turnbull BW, et al.

JAMA. 1996 Dec 25; 276(24):1957-63.

OBJECTIVE: To determine whether a nutritional supplement of selenium will decrease the incidence of cancer. DESIGN: A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial. SETTING: Seven dermatology clinics in the eastern United States. PATIENTS: A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years. INTERVENTIONS: Oral administration of 200 microg of selenium per day or placebo. MAIN OUTCOME MEASURES: The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers. RESULTS: After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR; 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred. CONCLUSIONS: Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made

n-6 and n-3 polyunsaturated fatty acids differentially modulate oncogenic Ras activation in colonocytes.

Collett ED, Davidson LA, Fan YY, et al.

Am J Physiol Cell Physiol. 2001 May; 280(5):C1066-C1075.

Ras proteins are critical regulators of cell function, including growth, differentiation, and apoptosis, with membrane localization of the protein being a prerequisite for malignant transformation. We have recently demonstrated that feeding fish oil, compared with corn oil, decreases colonic Ras membrane localization and reduces tumor formation in rats injected with a colon carcinogen. Because the biological activity of Ras is regulated by posttranslational lipid attachment and its interaction with stimulatory lipids, we investigated whether docosahexaenoic acid (DHA), found in fish oil, compared with linoleic acid (LA), found in corn oil, alters Ras posttranslational processing, activation, and effector protein function in young adult mouse colon cells overexpressing H-ras (YAMC-ras). We show here that the major n-3 polyunsaturated fatty acid (PUFA) constituent of fish oil, DHA, compared with LA (an n-6 PUFA), reduces Ras localization to the plasma membrane without affecting posttranslational lipidation and lowers GTP binding and downstream p42/44(ERK)-dependent signaling. In view of the central role of oncogenic Ras in the development of colon cancer, the finding that n-3 and n-6 PUFA differentially modulate Ras activation may partly explain why dietary fish oil protects against colon cancer development

Distal colonic neoplasms predict proximal neoplasia in average-risk, asymptomatic subjects.

Collett JA, Platell C, Fletcher DR, et al.

J Gastroenterol Hepatol. 1999 Jan; 14(1):67-71.

Flexible sigmoidoscopy has been recommended as a screening method to reduce the incidence of colorectal cancer in asymptomatic, average-risk subjects through the early detection and removal of polyps. However, the association between distal and proximal colonic neoplasia and, hence, the requirement for colonoscopic follow up of screen-detected distal neoplasms is unclear. Our aims were: (i) to evaluate the risk of having proximal neoplasms in those with distal colonic neoplasms; and (ii) to determine whether the risk was dependent on the number, size, histology or morphology of the distal lesions. We prospectively evaluated asymptomatic subjects in a flexible sigmoidoscopy based screening programme. Those with rectosigmoid neoplasia underwent colonoscopy. The number, size, histology and morphology of the polyps were recorded. Advanced lesions were defined as adenomas > 1 cm or with a villous component or severe dysplasia, carcinoma in situ or cancer. Adenomatous polyps were found in 17% (135) of screening flexible sigmoidoscopies. At colonoscopy, up to 30% of subjects with distal colonic neoplasms had synchronous proximal lesions at colonoscopy and up to 20% had advanced proximal lesions. The risk of proximal colonic neoplasia was increased in those with distal sessile colonic neoplasms but appeared independent of distal lesion size, number or morphology. In conclusion, distal colonic neoplasia predicts proximal neoplasia in up to 30% of subjects and these were advanced lesions in up to 20%. We recommend that all subjects with biopsy proven distal colonic neoplasia undergo colonoscopy

Point: From animal models to prevention of colon cancer. Systematic review of chemoprevention in min mice and choice of the model system.

Corpet DE, Pierre F.

Cancer Epidemiol Biomarkers Prev. 2003 May; 12(5):391-400.

The Apc(Min/+) mouse model and the azoxymethane (AOM) rat model are the main animal models used to study the effect of dietary agents on colorectal cancer. We reviewed recently the potency of chemopreventive agents in the AOM rat model (D. E. Corpet and S. Tache, Nutr. Cancer, 43: 1-21, 2002). Here we add the results of a systematic review of the effect of dietary and chemopreventive agents on the tumor yield in Min mice. The review is based on the results of 179 studies from 71 articles and is displayed also on the internet http://corpet.net/min.(2) We compared the efficacy of agents in the Min mouse model and the AOM rat model, and found that they were correlated (r = 0.66; P < 0.001), although some agents that afford strong protection in the AOM rat and the Min mouse small bowel increase the tumor yield in the large bowel of mutant mice. The agents included piroxicam, sulindac, celecoxib, difluoromethylornithine, and polyethylene glycol. The reason for this discrepancy is not known. We also compare the results of rodent studies with those of clinical intervention studies of polyp recurrence. We found that the effect of most of the agents tested was consistent across the animal and clinical models. Our point is thus: rodent models can provide guidance in the selection of prevention approaches to human colon cancer, in particular they suggest that polyethylene glycol, hesperidin, protease inhibitor, sphingomyelin, physical exercise, epidermal growth factor receptor kinase inhibitor, (+)-catechin, resveratrol, fish oil, curcumin, caffeate, and thiosulfonate are likely important preventive agents

A randomized, controlled chemoprevention trial of selenium in familial prostate cancer: Rationale, recruitment, and design issues.

Costello AJ.

Urology. 2001 Apr; 57(4 Suppl 1):182-4.

Deficiencies of selenium have been associated with an increased cancer risk, and several clinical and animal trials have suggested that improved selenium nutrition may reduce the incidence of several kinds of cancer, including lung, colorectal, and breast. Results from recent trials also show an anticarcinogenic effect of selenium in the prostate. There is converging evidence from epidemiologic, experimental animal, and molecular biology studies for an antitumor effect of selenium. Evidence suggests there are two modes of action of selenium affecting cancer risk: first, by functioning as an essential nutrient that provides the catalytic centers of a number of selenoenzymes, including some with antioxidant and redox functions; second, by serving as a source of selenium metabolytes that affect carcinogenesis in other ways. The first mechanism appears most relevant to protection against cancer initiation, the second against cancer progression. There is conclusive evidence of the increased risk of prostate cancer for a male with a family history of the disease. As a result of this evidence, and the evidence supporting the chemopreventive properties of selenium, this study proposed that a trial to test the effect of selenium on men at high risk for development of prostate cancer is appropriate. This article describes the Australian Prostate Cancer Prevention Trial Using Selenium (APPOSE) trial to test the hypothesis that daily dietary supplementation with selenium will reduce prostate cancer incidence in a population of men who are at increased risk because of a first-degree relative with prostate cancer

Computed tomographic colonography (virtual colonoscopy): a multicenter comparison with standard colonoscopy for detection of colorectal neoplasia.

Cotton PB, Durkalski VL, Pineau BC, et al.

JAMA. 2004 Apr 14; 291(14):1713-9.

CONTEXT: Conventional colonoscopy is the best available method for detection of colorectal cancer; however, it is invasive and not without risk. Computed tomographic colonography (CTC), also known as virtual colonoscopy, has been reported to be reasonably accurate in the diagnosis of colorectal neoplasia in studies performed at expert centers. OBJECTIVE: To assess the accuracy of CTC in a large number of participants across multiple centers. DESIGN, SETTING, AND PARTICIPANTS: A nonrandomized, evaluator-blinded, noninferiority study design of 615 participants aged 50 years or older who were referred for routine, clinically indicated colonoscopy in 9 major hospital centers between April 17, 2000, and October 3, 2001. The CTC was performed by using multislice scanners immediately before standard colonoscopy; findings at colonoscopy were reported before and after segmental unblinding to the CTC results. MAIN OUTCOME MEASURES: The sensitivity and specificity of CTC and conventional colonoscopy in detecting participants with lesions sized at least 6 mm. Secondary outcomes included detection of all lesions, detection of advanced lesions, possible technical confounders, participant preferences, and evidence for increasing accuracy with experience. RESULTS: A total of 827 lesions were detected in 308 of 600 participants who underwent both procedures; 104 participants had lesions sized at least 6 mm. The sensitivity of CTC for detecting participants with 1 or more lesions sized at least 6 mm was 39.0% (95% confidence interval [CI], 29.6%-48.4%) and for lesions sized at least 10 mm, it was 55.0% (95% CI, 39.9%-70.0%). These results were significantly lower than those for conventional colonoscopy, with sensitivities of 99.0% (95% CI, 97.1%->99.9%) and 100%, respectively. A total of 496 participants were without any lesion sized at least 6 mm. The specificity of CTC and conventional colonoscopy for detecting participants without any lesion sized at least 6 mm was 90.5% (95% CI, 87.9%-93.1%) and 100%, respectively, and without lesions sized at least 10 mm, 96.0% (95% CI, 94.3%-97.6%) and 100%, respectively. Computed tomographic colonography missed 2 of 8 cancers. The accuracy of CTC varied considerably between centers and did not improve as the study progressed. Participants expressed no clear preference for either technique. CONCLUSIONS: Computed tomographic colonography by these methods is not yet ready for widespread clinical application. Techniques and training need to be improved

Inflammation and cancer.

Coussens LM, Werb Z.

Nature. 2002 Dec 19; 420(6917):860-7.

Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development

DNA methylation as an intermediate biomarker in colorectal cancer: modulation by folic acid supplementation.

Cravo M, Fidalgo P, Pereira AD, et al.

Eur J Cancer Prev. 1994 Nov; 3(6):473-9.

Several studies have suggested that DNA hypomethylation is an early step in colorectal carcinogenesis. However, it is not clear at which stage in carcinogenesis this hypomethylation occurs, what promotes it, the extent to which it can be reversed and the consequences of such reversal in affecting tumour development. In an attempt to address some of these questions, we studied three groups of subjects with similar age and gender distributions: a group of 12 patients with colorectal carcinomas; a group of 12 patients with colorectal adenomas; and a group of eight healthy control subjects. Two experimental protocols were employed. In the first protocol, intrinsic DNA methylation was evaluated in neoplastic and in normal-appearing rectal mucosa of patients with colonic carcinomas or adenomas, compared with a group of healthy controls. In the second protocol, we examined, in a prospective and controlled fashion, the effect of folic acid supplementation (10 mg/day) on the degree of DNA methylation of rectal mucosa from those same patients after removal of the neoplasms. The degree of intrinsic DNA methylation was assessed on the basis of the capacity of the DNA isolates to serve as methyl acceptors in in vitro incubations that contained DNA methylase and [3H-methyl] S-adenosylmethionine. Intrinsic DNA methylation was significantly lower in carcinomas than in adenomas (P < 0.005). In addition, normal-appearing rectal mucosa from patients with carcinomas was significantly less methylated than in healthy controls (P < 0.005); the mean value found in the latter was also greater than the value observed in patients with adenomas, but not significantly so (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of folate supplementation on DNA methylation of rectal mucosa in patients with colonic adenomas: correlation with nutrient intake.

Cravo ML, Pinto AG, Chaves P, et al.

Clin Nutr. 1998 Apr; 17(2):45-9.

We have evaluated the effect of folate supplementation (5 mg/day) on global deoxyribonucleic acid (DNA) methylation status of the rectal mucosa of 20 patients with resected colonic adenomas in a prospective, controlled, cross-over study. Baseline values of DNA methylation were inversely correlated with caloric (P = 0.03) and fat intake (P = 0.05) and patients harbouring multiple polyps consumed significantly more calories (P = 0.0006), fat (P = 0.009) and carbohydrates (P = 0.009) as compared to patients having one single lesion. Folate supplementation resulted in a significant decrease of DNA hypomethylation in 7/20 patients (P = 0.05) which returned to previous values after placebo treatment. This effect was significantly correlated with number of polyps, with all the responders presenting one single lesion, whereas 8/13 of the non-responders had multiple ones (chi2 = 7.17, P = 0.007). In conclusion, folate supplementation may decrease degree of DNA hypomethylation, but only in patients with one single polyp. In those with multiple lesions, other nutritional factors such as caloric and fat intake, may be more determinant

The role of cyclooxygenase and lipoxygenase in cancer chemoprevention.

Cuendet M, Pezzuto JM.

Drug Metabol Drug Interact. 2000; 17(1-4):109-57.

The involvement of prostaglandins (PGs) and other eicosanoids in the development of human cancer has been known for over two decades. Importantly, an increase in PG synthesis may influence tumor growth in human beings and experimental animals, and numerous studies have illustrated the effect of PG synthesis on carcinogen metabolism, tumor cell proliferation and metastatic potential. PGs produced by cyclooxygenases (COXs) are represented by a large series of compounds that mainly enhance cancer development and progression, acting as carcinogens or tumor promoters, with profound effects on carcinogenesis. Further investigations suggest that arachidonic acid (AA) metabolites derived from lipoxygenase (LOX) pathways play an important role in growth-related signal transduction, implying that intervention through these pathways should be useful for arresting cancer progression. We discuss here the implications of COX and LOX in colon, pancreatic, breast, prostate, lung, skin, urinary bladder and liver cancers. Select inhibitors of COX and LOX are described, including nonsteroidal antiinflammatory drugs (NSAIDs), selective COX-2 inhibitors, curcumin, tea, silymarin and resveratrol, as well as a method useful for evaluating inhibitors of COX. Although a substantial amount of additional work is required to yield a better understanding of the role of COX and LOX in cancer chemoprevention, it is clear that beneficial therapeutic effects can be realized through drug-mediated modulation of these metabolic pathways

Immunology and immunotherapy of colorectal cancer.

Dalerba P, Maccalli C, Casati C, et al.

Crit Rev Oncol Hematol. 2003 Apr; 46(1):33-57.

This review critically discusses data on immunology of colorectal cancer, starting from pathology and molecular biology, and then considering the molecular characterisation of colon cancer antigens and the clinical trials of immunotherapy. A careful evaluation of histopathological studies on intra-epithelial infiltration by T cells in primary tumours, together with the analysis of HLA expression by colorectal cancer cells, suggest that anti-tumour T cell immune responses may take place in vivo in those patients, influencing prognosis and shaping the tumour immunological profile. Moreover, the molecular characterisation of tumour antigens expressed by colorectal carcinomas, together with improved understanding of mechanisms of the immune response and more sensitive methods for the in vivo detection of T cell responses, are now allowing researchers to design new and more effective vaccination protocols, with encouraging preliminary results. By drawing together the experimental evidence from different research fields, this review provides support for the concept that colorectal carcinoma is immunogenic and may reasonably be considered as a target for immunotherapy, and attempts to address critical issues and envisage future developments in this challenging research field

Early detection and prevention of colorectal cancer (review).

Dashwood RH.

Oncol Rep. 1999 Mar; 6(2):277-81.

Colorectal cancer is a leading cause of cancer-related deaths, and the two most important considerations for avoidance of this disease are early detection and prevention. If metastasis has occurred to distant sites, such as the liver and lung, the 5-year survival rate for colorectal cancer is below 10%, but this increases to greater than 90% when the cancer is found early. Early detection can be facilitated by use of the digital rectal exam, fecal occult blood test, sigmoidoscopy, and colonoscopy, but these methods might be supplemented in the future by other screening assays using intermediate biomarkers. One interesting biomarker, the aberrant crypt focus (ACF), has been observed in resected human colons, and is the earliest detectable morphological change in the colons of experimental animals treated with carcinogens such as the cooked meat heterocyclic amines. The ACF can also be used as an end-point to screen for potential inhibitors of colorectal cancer; using this approach, we identified conjugated linoleic acids, indole-3-carbinol, chlorophyllin, and tea polyphenols as promising inhibitors in the colon. These compounds can be added to a growing list of natural and synthetic agents that might be effective against colorectal cancer, including selenium, calcium, and nonsteroidal anti-inflammatory agents. However, results from human clinical trials with several of these compounds have highlighted the need for detailed mechanism data before recommendations can be made for wide-scale use in humans. In the meantime, the best approach to reducing the risk of colorectal cancer would be to increase the dietary intake of fruits, vegetables and cereals, while reducing the overall intake of fat, particularly from animal sources

Dietary folate and selenium affect dimethylhydrazine-induced aberrant crypt formation, global DNA methylation and one-carbon metabolism in rats.

Davis CD, Uthus EO.

J Nutr. 2003 Sep; 133(9):2907-14.

Several observations suggest a role for DNA methylation in cancer pathogenesis. Although both selenium and folate deficiency have been shown to cause global DNA hypomethylation and increased cancer susceptibility, the nutrients have different effects on one-carbon metabolism. Thus, the purpose of this study was to investigate the interactive effects of dietary selenium and folate. Weanling, Fischer-344 rats (n = 23/diet) were fed diets containing 0 or 2.0 mg selenium (as selenite)/kg and 0 or 2.0 mg folate/kg in a 2 x 2 factorial design. After 3 and 4 wk of a 12-wk experiment, 19 rats/diet were injected intraperitoneally with dimethylhydrazine (DMH, 25 mg/kg) and 4 rats/diet were administered saline. Selenium deficiency decreased (P < 0.05) colonic DNA methylation and the activities of liver DNA methyltransferase and betaine homocysteine methyltransferase and increased plasma glutathione concentrations. Folate deficiency increased (P < 0.05) the number of aberrant crypts per aberrant crypt foci, the concentration of colonic S-adenosylhomocysteine and the activity of liver cystathionine synthase. Selenium and folate interacted (P < 0.0001) to influence one-carbon metabolism and cancer susceptibility such that the number of aberrant crypts and the concentrations of plasma homocysteine and liver S-adenosylhomocysteine were the highest and the concentrations of plasma folate and liver S-adenosylmethionine and the activity of liver methionine synthase were the lowest in rats fed folate-deficient diets and supplemental selenium. These results suggest that selenium deprivation ameliorates some of the effects of folate deficiency, probably by shunting the buildup of homocysteine (as a result of folate deficiency) to glutathione

Resveratrol, a chemopreventive agent, disrupts the cell cycle control of human SW480 colorectal tumor cells.

Delmas D, Passilly-Degrace P, Jannin B, et al.

Int J Mol Med. 2002 Aug; 10(2):193-9.

Resveratrol is a natural polyphenolic compound produced by a number of plants and found in high amount in peanuts, seeds, grapes or berries as source of human nutrition. Epidemiological studies strongly suggest that resveratrol may act as a cancer chemopreventive compound. The mechanism by which resveratrol inhibits cell proliferation was studied in human colorectal tumor SW480 cell line. The results show that resveratrol strongly inhibits cell proliferation at the micromolar range in a time- and dose-dependent manner. Resveratrol appears to block the cell cycle at the transition --> G2/M since inhibition of [(3)H]-thymidine incorporation is not observed, while there is an increase of the cell number in S phase. During this inhibition process, resveratrol increases the content of cyclins A and B1 as well as cyclin-dependent kinases Cdk1 and Cdk2. Moreover, resveratrol promotes Cdk1 phosphorylation. In conclusion, resveratrol exerts a strong inhibition of SW480 human colorectal tumor cell proliferation at least by modulating cyclin and cyclin-dependent kinase activities

The influence of tumor lymphocytic infiltration on long term survival of surgically treated colorectal cancer patients.

Di Giorgio A, Botti C, Tocchi A, et al.

Int Surg. 1992 Oct; 77(4):256-60.

Prognostic significance of host-immune response, as gathered by the degree of tumour lymphocytic infiltration (TLI), and its relationship to other prognostic variables were investigated in 361 colorectal cancer patients admitted to our Institution for curative resection from January 1960 to December 1978. The presence of a local immune reactivity was significantly related to a less advanced stage of disease and a better differentiated tumour. A poorer prognosis was detected in patients with minor or no lymphocytic infiltration. TLI was the single most important prognostic parameter, according to the Cox model and to logistic regression analysis. These findings suggest that also TLI should be considered in the current Staging System of colorectal cancer

[18F-Fluorodeoxyglucose positron emission tomography in restaging of colorectal cancer].

Dietlein M, Weber W, Schwaiger M, et al.

Nuklearmedizin. 2003 Aug; 42(4):145-56.

AIM, METHOD: Recommendations for the use of FDG-PET in relapsed colorectal cancer and the decision of reimbursement should base on published studies and on their level of evidence. Therefore, the PET-studies published between 1997 and 2002 were graded by the bias-criteria, by two rating-systems and by two classification-systems for the level of evidence according to AHCPR (Agency for Health Care Policy and Research) and VHA (Veterans Health Administration). RESULTS: The recommendation for the use of PET in relapsed colorectal cancer reached the level IIa according to the AHCPR, corresponding to level B according to the VHA. The sensitivity and specificity of FDG-PET were 94% (95% CI: 91-96%) and 78% (95% CI: 69-86%), respectively. Staging was changed correctly in 27% of patients (95% CI: 24-30%). Staging by FDG-PET was incorrect in 4% of the patients (95% CI: 2-5%) compared with the conventional methods. The additional use of PET changed the prospectively defined management plan for 34% of patients (95% CI: 31-38%). Either potentially curative operations were initiated in case of resectable tumour or futile operations were cancelled in case of multiple metastases. CONCLUSION: The 3-year-survival-rate following surgery would have exceeded 70% if the selection of patients had included an additional PET-examination. The correct selection of patients is requested in the daily routine as well as in the clinical implementation of neoadjuvant therapies to prevent a selection-bias from a suboptimal restaging without PET

N;-3 and n;-6 polyunsaturated fatty acids induce cytostasis in human urothelial cells independent of p53 gene function.

Diggle CP, Pitt E, Roberts P, et al.

J Lipid Res. 2000 Sep; 41(9):1509-15.

The role of long-chain polyunsaturated fatty acids (PUFA) in the etiopathology and treatment of cancer is poorly understood. We have studied the effects of n;-3 and n;-6 PUFA on the proliferation and survival of normal human uroepithelial (NHU) cells, cells with disabled p53 function after stable transfection with the human papillomavirus 16 (HPV16) E6 gene (HU-E6), and p53-disabled cells that had passed through crisis and acquired karyotypic abnormalities (HU-E6P). The n;-3 and n;-6 PUFA had distinct reversible antiproliferative and irreversible cytostatic effects according to concentration and exposure time. The reversible antiproliferative effect was partly due to the production of lipoxygenase metabolites. NHU and HU-E6 cells were equally sensitive to n;-3 and n;-6 PUFA, but HU-E6P cells were more resistant to both the antiproliferative and cytostatic effects. Cytostatic concentrations of n;-3 and n;-6 PUFA did not induce apoptosis, but caused permanent growth arrest ("interphase" or "reproductive" cell death) and mRNA levels for genes involved in cell cycle control (p21, p16, p27, cdk1, cdk2, and cdk4) were not altered. Neither n;-3 nor n;-6 PUFA promoted acquisition of karyotypic abnormalities in HU-E6 cells, suggesting that n;-3 and n;-6 PUFA do not cause genotoxic damage.In conclusion, our studies show that the antiproliferative and cytostatic effects of n;-3 and n;-6 PUFA are not dependent on p53 function and, further, that transformation results in a loss of sensitivity to n;-3 and n;-6 PUFA-mediated growth inhibition

Colorectal cancer in women: an underappreciated but preventable risk.

Donovan JM, Syngal S.

J Womens Health. 1998 Feb; 7(1):45-8.

Colorectal cancer is the third most common non-skin malignancy in women, after breast and lung cancer. Although approximately 40% of the 65,000 women diagnosed each year eventually die of the disease, colon cancer is highly curable when diagnosed at an early stage. Moreover, because the majority of colon cancers arise in previously benign colonic polyps, there is a substantial period, up to several years, in which removal of polyps can reduce the risk of colon cancer. Recently, the United States Preventive Task Force recommended universal screening for colon cancer after age 50. Strong evidence from randomized controlled trials and case-control studies supports use of annual testing for occult blood in stool and flexible sigmoidoscopy every 5-7 years. Although the risk of colon cancer is similar in men and women, women frequently have the perception that colorectal cancer is a man's disease. Partially in consequence, women are less likely than men to undergo screening sigmoidoscopy. Further barriers include primary care providers' lack of awareness of updated guidelines and patients' lack of compliance with multiple screening tests and their fear of discomfort. Because the risk of colorectal cancer can be reduced by up to 75% in those who undergo screening and subsequent surveillance to remove further polyps, it is crucial that women be targeted to undergo screening tests for colorectal cancer

Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial.

Duffield-Lillico AJ, Dalkin BL, Reid ME, et al.

BJU Int. 2003 May; 91(7):608-12.

OBJECTIVE: To present the results (to January 1996, the end of blinded treatment) of the Nutritional Prevention of Cancer (NPC) Trial, a randomized trial of selenium (200 micro g daily) designed to test the hypothesis that selenium supplementation (SS) could reduce the risk of recurrent nonmelanoma skin cancer among 1312 residents of the Eastern USA. MATERIALS AND METHODS: Original secondary analyses of the NPC to 1993 showed striking inverse associations between SS and prostate cancer incidence. A subsequent report revealed that this effect was accentuated among men with the lowest baseline plasma selenium concentrations. The effects of treatment overall and within subgroups of baseline prostate-specific antigen (PSA) and plasma selenium concentrations were examined using incidence rate ratios and Cox proportional hazards models. RESULTS: SS continued to significantly reduce the overall incidence (relative risk and 95% confidence interval) of prostate cancer (0.51, 0.29-0.87). The protective effect of SS appeared to be confined to those with a baseline PSA level of < or= 4 ng/mL (0.35, 0.13-0.87), although the interaction of baseline PSA and treatment was not statistically significant. Participants with baseline plasma selenium concentrations only in the lowest two tertiles (< 123.2 ng/mL) had significant reductions in prostate cancer incidence. A significant interaction between baseline plasma selenium and treatment was detected. CONCLUSION: To the end of the blinded treatment the NPC trial continued to show a significant protective effect of SS on the overall incidence of prostate cancer, although the effect was restricted to those with lower baseline PSA and plasma selenium concentrations

Clinical utility of biochemical markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines.

Duffy MJ, van Dalen A, Haglund C, et al.

Eur J Cancer. 2003 Apr; 39(6):718-27.

In recent years, numerous serum and cell/tissue-based markers have been described for colorectal cancer (CRC). The aim of this article was to provide guidelines for the routine clinical use of some of these markers. Lack of sensitivity and specificity preclude the use of any available serum markers such as carcinoembryonic antigen (CEA), CA 19-9, CA 242, CA 72-4, tissue polypeptide antigen (TPA) or tissue polypeptide-specific antigen (TPS) for the early detection of CRC. However, preoperative measurement of CEA is desirable as this may give independent prognostic information, help with surgical management and provide a baseline level for subsequent determinations. For patients with stage 2 (Dukes' B) and 3 (Dukes' C) disease who may be candidates for liver resection, CEA levels should be measured every 2-3 months for at least 3 years after diagnosis. For monitoring treatment of advanced disease, CEA should also be tested every 2-3 months. Insufficient evidence is presently available to recommend the routine use of other serum markers for monitoring purposes. Similarly, the new cell and tissue-based markers (e.g, ras, P53) cannot yet be recommended for routine clinical use

Screening for and staging of cancer: a statement by the American Joint Committee for Cancer Staging and End Results Reporting.

Editorial.

CA Cancer J Clin. 1980; 30(6 Nov-Dec):324-5.

No abstract :- Editorial

The protective role of selenium on genetic damage and on cancer.

El Bayoumy K.

Mutat Res. 2001 Apr 18; 475(1-2):123-39.

Collectively, results from epidemiologic studies, laboratory bioassays, and human clinical intervention trials clearly support a protective role of selenium against cancer development. Several hypotheses have been proposed to explain these observations. Increased genomic instability, either inherent or induced by exogenous agents (mutagens or carcinogens), has been considered as a primary event leading to neoplastic transformation. This report deals specifically with the evidence for a role of selenium in the inhibition of carcinogen-induced covalent DNA adduct formation and retardation of oxidative damage to DNA, lipids and proteins, and for modulating cellular and molecular events that are critical in cell growth inhibition and in the multi-step carcinogenesis process. At present, the bulk of our knowledge on the role of selenium on genetic stability is based primarily on animal data and from studies conducted in in vitro systems. Studies performed in vitro showed that the dose and form of selenium compounds are critical factors with regard to cellular responses. Inorganic (at doses up to 10microM) and organic selenium compounds (at doses equal to or greater than 10microM) elicit distinctly different cellular responses. The recommended daily allowance (RDA) is 50-70 microgramSe per day for healthy adults; with 40 microgramSe as minimum requirement. Less than 11 microgramSe will definitely put people at risk of deficiency that would be expected to cause genetic damage. Daily doses of 100-200 microgramSe inhibited genetic damage and cancer development in humans. About 400 microgramSe per day is considered an upper limit. Clearly, doses above the RDA are needed to inhibit genetic damage and cancer. However, it has been hypothesized that the intake of excessive doses of selenium may cause oxidative damage, leading to genomic instability. The use of a cocktail consisting of selenium, and other vitamins and minerals appears to be a promising approach to inhibit genetic damage and the development of cancer. It is the author's recommendation that development of mechanism-based hypotheses that can be tested in pilot studies in different populations prior to a large-scale clinical trial in humans, is of paramount importance in order to better understand the role of selenium on genetic stability and cancer

The chemoprevention of cancer by mevalonate-derived constituents of fruits and vegetables.

Elson CE, Yu SG.

J Nutr. 1994 May; 124(5):607-14.

Anutritive isoprenoid constituents of fruits, vegetables, cereal grains and essential oils exhibit a spectrum of anticarcinogenic activities. The induction of hepatic Phase II detoxifying activities by dietary isoprenoids appears to underlie their blocking action. The second anticarcinogenic action of the dietary isoprenoids, suppression of the growth of chemically initiated and transplanted tumors is, we suggest, secondary to the inhibition of mevalonate pathway activities. Mevinolin, a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase activity, depletes cells of the intermediate products of the pathway that are required for the posttranslational modification of proteins, a process giving the proteins lipophilic anchors that bind to membranes. As a consequence, nuclear lamins and ras oncoproteins remain in nascent states, and cells do not proliferate. gamma-Tocotrienol, perillyl alcohol, geraniol and d-limonene suppress hepatic HMG-CoA reductase activity, a rate-limiting step in cholesterol synthesis, and modestly lower serum-cholesterol levels of animals. These isoprenoids also suppress tumor growth. The HMG-CoA reductase of neoplastic tissues differs from that of sterologenic tissues in being markedly resistant to sterol feedback inhibition. Our review suggests that the mevalonate pathway of tumor tissues is uniquely sensitive to the inhibitory actions of the dietary isoprenoids

The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells.

Endres S, Ghorbani R, Kelley VE, et al.

N Engl J Med. 1989 Feb 2; 320(5):265-71.

We examined whether the synthesis of interleukin-1 or tumor necrosis factor, two cytokines with potent inflammatory activities, is influenced by dietary supplementation with n-3 fatty acids. Nine healthy volunteers added 18 g of fish-oil concentrate per day to their normal Western diet for six weeks. We used a radioimmunoassay to measure interleukin-1 (IL-1 beta and IL-1 alpha) and tumor necrosis factor produced in vitro by stimulated peripheral-blood mononuclear cells. With endotoxin as a stimulus, the synthesis of IL-1 beta was suppressed from 7.4 +/- 0.9 ng per milliliter at base line to 4.2 +/- 0.5 ng per milliliter after six weeks of supplementation (43 percent decrease; P = 0.048). Ten weeks after the end of n-3 supplementation, we observed a further decrease to 2.9 +/- 0.5 ng per milliliter (61 percent decrease; P = 0.005). The production of IL-1 alpha and tumor necrosis factor responded in a similar manner. Twenty weeks after the end of supplementation, the production of IL-1 beta, IL-1 alpha, and tumor necrosis factor had returned to the presupplement level. The decreased production of interleukin-1 and tumor necrosis factor was accompanied by a decreased ratio of arachidonic acid to eicosapentaenoic acid in the membrane phospholipids of mononuclear cells. We conclude that the synthesis of IL-1 beta, IL-1 alpha, and tumor necrosis factor can be suppressed by dietary supplementation with long-chain n-3 fatty acids. The reported antiinflammatory effect of these n-3 fatty acids may be mediated in part by their inhibitory effect on the production of interleukin-1 and tumor necrosis factor

Diet and colorectal cancer: an investigation of the lectin/galactose hypothesis 357 1157.

Evans RC, Fear S, Ashby D, et al.

Gastroenterology. 2002 Jun; 122(7):1784-92.

BACKGROUND & AIMS: Mucosal expression of terminal unsubstituted galactose is increased in colon cancer and precancer and allows interaction with mitogenic galactose-binding lectins of dietary or microbial origin. This study tests the hypothesis that galactose, which is variably plentiful in fruit and vegetable but not cereal fibers, might prevent cancer by binding and inhibiting such lectins. METHODS: Colorectal cancer cases (512) and controls (512) were matched for age, sex, primary care practitioner, and postal code. A 160-item food-frequency questionnaire was used to estimate their usual pre-illness (6 months previous) diet, aspirin intake, and exercise. RESULTS: Neither cereal fiber nor fruit and vegetable fiber were protective when assessed by univariate analysis, whereas dietary fiber galactose content showed a dose-related protective effect (odds ratio [OR] highest quartile/lowest quartile, 0.67; confidence interval [CI], 0.47-0.95) that remained protective when adjusted for energy, red meat, alcohol, calcium, protein and fat intake, regular aspirin usage, and exercise. Intake of nonlegume green vegetables, assessed because of the high lectin content of legumes, was also protective (OR, 0.54; CI, 0.35-0.81), but this was not independent of galactose. Protective effects of exercise and regular daily aspirin consumption and harmful effects of high energy consumption and high red meat intake were confirmed. CONCLUSIONS: The protective effect of fruit and vegetable fibers may be related to their galactose content. This provides further evidence that the association between diet and colon cancer is mediated via specific food components and may explain the discrepant results of studies addressing the protective effects of fiber

Effect of a protein and energy dense N-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial.

Fearon KC, Von Meyenfeldt MF, Moses AG, et al.

Gut. 2003 Oct; 52(10):1479-86.

AIM: N-3 fatty acids, especially eicosapentaenoic acid (EPA), may possess anticachectic properties. This trial compared a protein and energy dense supplement enriched with n-3 fatty acids and antioxidants (experimental: E) with an isocaloric isonitrogenous control supplement (C) for their effects on weight, lean body mass (LBM), dietary intake, and quality of life in cachectic patients with advanced pancreatic cancer. METHODS: A total of 200 patients (95 E; 105 C) were randomised to consume two cans/day of the E or C supplement (480 ml, 620 kcal, 32 g protein +/- 2.2 g EPA) for eight weeks in a multicentre, randomised, double blind trial. RESULTS: At enrolment, patients' mean rate of weight loss was 3.3 kg/month. Intake of the supplements (E or C) was below the recommended dose (2 cans/day) and averaged 1.4 cans/day. Over eight weeks, patients in both groups stopped losing weight (delta weight E: -0.25 kg/month versus C: -0.37 kg/month; p = 0.74) and LBM (Delta LBM E: +0.27 kg/month versus C: +0.12 kg/month; p = 0.88) to an equal degree (change from baseline E and C, p<0.001). In view of evident non-compliance in both E and C groups, correlation analyses were undertaken to examine for potential dose-response relationships. E patients demonstrated significant correlations between their supplement intake and weight gain (r = 0.50, p<0.001) and increase in LBM (r = 0.33, p = 0.036). Such correlations were not statistically significant in C patients. The relationship of supplement intake with change in LBM was significantly different between E and C patients (p = 0.043). Increased plasma EPA levels in the E group were associated with weight and LBM gain (r = 0.50, p<0.001; r = 0.51, p = 0.001). Weight gain was associated with improved quality of life (p<0.01) only in the E group. CONCLUSION: Intention to treat group comparisons indicated that at the mean dose taken, enrichment with n-3 fatty acids did not provide a therapeutic advantage and that both supplements were equally effective in arresting weight loss. Post hoc dose-response analysis suggests that if taken in sufficient quantity, only the n-3 fatty acid enriched energy and protein dense supplement results in net gain of weight, lean tissue, and improved quality of life. Further trials are required to examine the potential role of n-3 enriched supplements in the treatment of cancer cachexia

Hypomethylation of ras oncogenes in primary human cancers.

Feinberg AP, Vogelstein B.

Biochem Biophys Res Commun. 1983 Feb 28; 111(1):47-54.

We have examined the methylation status of two cellular oncogenes, c-Ha-ras and c-Ki-ras, in primary human carcinomas and the adjacent analogous normal tissues from which the tumors derived. The c-Ha-ras gene was hypomethylated in six of eight carcinomas, including five colonic adenocarcinomas and one small cell lung carcinoma, when compared to adjacent normal tissues. The c-Ki-ras gene was hypomethylated to a lesser extent in two colonic adenocarcinomas. This is the first demonstration of alterations in methylation of cellular oncogenes in human cancer

Dietary selenium reduces the formation of aberrant crypts in rats administered 3,2'-dimethyl-4-aminobiphenyl.

Feng Y, Finley JW, Davis CD, et al.

Toxicol Appl Pharmacol. 1999 May 15; 157(1):36-42.

Human epidemiologic studies suggest that low selenium status is associated with increased cancer risk and that selenium supplementation is associated with reduction in the incidence of several cancers, including colorectal cancer. Aromatic and heterocyclic amine carcinogens are thought to be important in the etiology of human colorectal cancer, but no information is available on the effects of selenium on aromatic amine-induced colon cancer. In order to investigate this effect, aberrant crypt foci (ACF), the putative preneoplastic lesions of colon cancer in humans and rodents, were used as a biomarker to test the hypothesis that selenium supplementation can reduce aromatic amine-induced colon carcinogenesis. Male weanling F344 inbred rats were fed a basal torula yeast selenium-deficient diet supplemented with 0, 0.1, or 2. 0 mg selenium/kg diet as selenite, selenate, or selenomethionine (SeMet). Animals were fed the diets for 4 weeks and then administered 1 sc injection/week for 2 weeks of 3, 2'-dimethyl-4-aminobiphenyl (DMABP; 100 mg/kg) or vehicle (peanut oil). At 12 weeks, the rats were euthanized and the colon and rectum were removed, opened longitudinally, and fixed in 70% ethanol. Glutathione peroxidase activities in erythrocytes and liver cytosol and selenium concentrations in the colon/rectum and kidney increased significantly (p < 0.05) and in a dose-dependent manner with each of the three selenium diets. No ACF were identified in vehicle-treated rats. In DMABP-treated rats, ACF frequencies decreased significantly (p < 0.05) in groups supplemented with 0.1 or 2.0 mg selenium/kg diet as selenite and selenate but not SeMet. There were no significant differences in ACF and aberrant crypts between rats fed 0.1 vs 2.0 mg selenium/kg diet. These results suggest that dietary selenium, depending on chemical form, can reduce aromatic amine-induced colon carcinogenesis

Modulatory effects of selenium and zinc on the immune system.

Ferencik M, Ebringer L.

Folia Microbiol (Praha). 2003; 48(3):417-26.

Almost all nutrients in the diet play a crucial role in maintaining an "optimal" immune response, and both insufficient and excessive intakes can have negative consequences on the immune status and susceptibility to a variety of pathogens. We summarize the evidence for the importance of two micronutrients, selenium and zinc, and describe the mechanisms through which they affect the immune status and other physiological functions. As a constituent of selenoproteins, selenium is needed for the proper functioning of neutrophils, macrophages, NK cells, T lymphocytes and some other immune mechanisms. Elevated selenium intake may be associated with reduced cancer risk and may alleviate other pathological conditions including oxidative stress and inflammation. Selenium appears to be a key nutrient in counteracting the development of virulence and inhibiting HIV progression to AIDS. It is required for sperm motility and may reduce the risk of miscarriage. Selenium deficiency has been linked to adverse mood states and some findings suggest that selenium deficiency may be a risk factor in cardiovascular diseases. Zinc is required as a catalytic, structural and regulatory ion for enzymes, proteins and transcription factors, and is thus a key trace element in many homeostatic mechanisms of the body, including immune responses. Low zinc ion bioavailability results in limited immunoresistance to infection in aging. Physiological supplementation of zinc for 1-2 months restores immune responses, reduces the incidence of infections and prolongs survival. However, in every single individual zinc supplementation of food should be adjusted to the particular zinc status in views of the great variability in habitat conditions, health status and dietary requirements

Serum selenium and risk of large size colorectal adenomas in a geographical area with a low selenium status.

Fernandez-Banares F, Cabre E, Esteve M, et al.

Am J Gastroenterol. 2002 Aug; 97(8):2103-8.

OBJECTIVE: Selenium is a fundamental nutrient to human health that might have anticarcinogenic effects. Previous studies have assessed the possible relationship of selenium status to colorectal adenomas with controversial results. We primarily aimed to assess the relationship of serum selenium status with the presence of large size colorectal adenomas in subjects living in a poor selenium region. The serum selenium status in colorectal cancer was also evaluated. METHODS: Serum selenium levels were measured in 28 patients with large size sporadic adenomatous polyps, 24 patients with colorectal adenocarcinomas, and 35 age-matched healthy individuals. A logistic regression analysis was performed to assess the relationship of serum selenium to colorectal adenomatous polyps after adjusting for confounding variables (age, sex, smoking habit, and alcohol drinking). RESULTS: Among subjects aged < or = 60 yr, mean serum selenium levels were significantly lower in both patient groups (adenoma, 57.9 +/- 4.3 microg/L; cancer, 43.7 +/- 6.6 microg/L) than in healthy controls (88.9 +/- 8 microg/L) (p = 0.0001). There were no difference among subjects > 60 yr old. A significant inverse association between selenium status and the diagnosis of large size adenomatous polyps after adjusting for confounding variables was found (adjusted p = 0.029). Subjects with higher selenium status (> or = 75th percentile value of 82.11 microg/L) had a lower probability (OR = 0.17, 95% CI = 0.03-0.84) to be in the adenoma group than subjects with lower selenium status (< 82.11 microg/L). This association was more marked in subjects aged < or = 60 yr (adjusted p value = 0.04, OR = 0.08, 95% CI = 0.007-0.91), and was not significant in older subjects. CONCLUSIONS: Results suggest that high selenium status may decrease the risk of large size adenomas in a low selenium region, and that this preventive effect seems to be exclusive to subjects < or = 60 yr. These results will need to be confirmed in additional epidemiological studies before recommending selenium supplementation in patients with colon adenomas

Dietary selenium repletion may reduce cancer incidence in people at high risk who live in areas with low soil selenium.

Fleet JC.

Nutr Rev. 1997 Jul; 55(7):277-9.

Studies examining the relationship between dietary selenium intake and risk of various cancers have shown that low selenium intake is associated with higher cancer rates. A recent well-controlled intervention trial studied whether selenium supplementation can prevent cancer in subjects who have a history of skin cancer and live in areas of the United States with low soil selenium levels. Selenium supplementation did not reduce skin cancer rates, but the incidence of total, lung, colorectal, and prostate cancers was significantly reduced by the intervention. Although these data need confirmation, they suggest that adequate selenium intake is essential for cancer prevention

Cholesterolemia in colorectal cancer.

Forones NM, Falcao JB, Mattos D, et al.

Hepatogastroenterology. 1998 Sep; 45(23):1531-4.

BACKGROUND/AIMS: Colorectal cancer incidence is higher in developed countries. High fat intake is one of the risk factors. However, many studies observed lower cholesterol serum levels on diagnosis of colorectal cancer. The aim of this assay was to study the serum cholesterol levels in patients with colorectal cancer and compare these values with individuals of the same age and sex. METHODOLOGY: Cholesterol serum levels of 85 patients with colorectal cancer were determined. Each of the patients with colorectal cancer were matched with an individual without cancer of the same age and sex. Total cholesterol concentrations were determined using an enzymatic colorimetric method. RESULTS: The mean serum of cholesterol was 183.4 for the colorectal group and 209.7 for the control group. This difference was statistically significant. This difference was more evident in patients with colon cancer and older than 60 years of age. There was no difference between the different Dukes' stage. CONCLUSIONS: Our study suggest an association between low blood cholesterol and colorectal cancer. We believe that the lower level of cholesterol observed in these patients is a consequence between the difference of colorectal carcinogenesis

The sentinel hyperplastic polyp: a marker for synchronous neoplasia in the proximal colon.

Foutch PG, DiSario JA, Pardy K, et al.

Am J Gastroenterol. 1991 Oct; 86(10):1482-5.

We prospectively screened 129 asymptomatic subjects (mean age 64 yr) with flexible sigmoidoscopy. Colonoscopy was performed at a later date, regardless of the sigmoidoscopic result. Our intent was 1) to establish the prevalence of proximal neoplasms in patients with and without hyperplastic polyps within reach of the 60-cm sigmoidoscope and 2) to determine whether a distal (sentinel) hyperplastic polyp predicts the presence of synchronous neoplastic polyps higher up in the colon. Our results show that 15% of asymptomatic adult subjects without polyps on sigmoidoscopy have adenomas in proximal colonic segments that can be diagnosed only by colonoscopy. By comparison, proximal neoplasms were detected in 32% (p less than 0.05) and 37% (p less than 0.05) of patients when hyperplastic or adenomatous polyps, respectively, were present on the sigmoidoscopic examination. This finding suggests that a distal (sentinel) hyperplastic polyp by itself may be a marker for neoplastic polyps in proximal colonic segments. Also, the "index" adenoma and "sentinel" hyperplastic polyp may be equivalent for predicting the presence of proximal neoplasms. The observed detection rates for these polyps were both significantly higher than expected when compared to patients who did not have polyps in the distal colon or rectum. If these results can be confirmed by a larger prospective trial, then full colonoscopy for detection of proximal neoplasms may be indicated when either an index adenoma or sentinel hyperplastic polyp is detected by sigmoidoscopy

Sulforaphane inhibits growth of a colon cancer cell line.

Frydoonfar HR, McGrath DR, Spigelman AD.

Colorectal Dis. 2004 Jan; 6(1):28-31.

OBJECTIVE: The consumption of cruciferous vegetables has a protective effect on the development of colorectal cancer. The phytochemical Sulforaphane is an isothiocyanate found almost exclusively in cruciferous vegetables. We have studied the effect of Sulforaphane on cell proliferation of an HT-29 colon cancer cell line. MATERIALS AND METHODS: HT-29 colon cancer cells were cultured in 96-well microtitre plates. Sulforaphane (in concentrations ranging from 0.01 to 0.1 mmol) were added to the wells. Cell proliferation was measured using the colourimetric assay technique. RESULTS: The proliferation of colon cancer cells was significantly reduced by Sulforaphane at concentrations of >/=0.02 mmol. CONCLUSION: These findings may help explain the epidemiologically proven protective effect of vegetables against colon cancer

Cancer inhibition by green tea.

Fujiki H, Suganuma M, Okabe S, et al.

Mutat Res. 1998 Jun 18; 402(1-2):307-10.

Green tea is now an acknowledged cancer preventive in Japan. This paper discusses several important features of (-)-epigallocatechin gallate (EGCG), the main constituent of green tea and tea polyphenols. EGCG and other tea polyphenols inhibited growth of human lung cancer cell line, PC-9 cells with G2/M arrest. 3H-EGCG administered by p.o. intubation into mouse stomach revealed that small amounts of 3H-activity were found in various organs where EGCG and green tea extract had previously demonstrated their anticarcinogenic effects, such as skin, stomach, duodenum, colon, liver, lung and pancreas. Cancer onset of patients who had consumed over 10 cups of green tea per day was 8.7 years later among females and 3.0 years later among males, compared with patients who had consumed under three cups per day. The mechanisms of action of EGCG were briefly discussed with regard to inhibition of tumor necrosis factor-alpha (TNF-alpha) release

[Study on the effects of curcumin on angiogenesis].

Gao C, Ding Z, Liang B, et al.

Zhong Yao Cai. 2003 Jul; 26(7):499-502.

OBJECTIVE: The effects of curcumin on angiogenesis were studied. METHODS: Proliferation of bovine aortic endothelial cells (BAECs) and cells of human cancerous cell line SGC-7901 were measured by MTT colorimetric assay after treated by various concentrations of curcumin. The effects of curcumin on BAECS proliferation promoted by tumor conditioned medium were observed by MTT colorimetric assay. The effects of various concentration of curcumin on the migration of BAECs and migration promoted by tumor conditioned medium were investigated by agorose assay. RESULTS: Curcumin can obviously inhibit the proliferation of BAECs induced by fetal bovine serum (FBS) and tumor conditioned medium. Curcumin can also obviously inhibit the migration of BAECs induced by FBS and tumor conditioned medium. CONCLUSION: Curcumin can inhibit angiogenesis by preventing proliferation and migration of endothelial cells. It also suggestes that curcumin is one kind of specific inhibitors of angiogenesis

Incorporation of polyunsaturated fatty acids into CT-26, a transplantable murine colonic adenocarcinoma.

Gaposchkin DP, Zoeller RA, Broitman SA.

Lipids. 2000 Feb; 35(2):181-6.

Previous studies in our laboratory have shown that marine oils, with high levels of eicosapentaenoic (EPA, 20:5n-3) and docosahexaenoic acids (DHA, 22:6n-3), inhibit the growth of CT-26, a murine colon carcinoma cell line, when implanted into the colons of male BALB/c mice. An in vitro model was developed to study the incorporation of polyunsaturated fatty acids (PUFA) into CT-26 cells in culture. PUFA-induced changes in the phospholipid fatty acid composition and the affinity with which different fatty acids enter the various phospholipid species and subspecies were examined. We found that supplementation of cultured CT-26 cells with either 50 microM linoleic acid (LIN, 18:2n-6), arachidonic acid (AA, 20:4n-6), EPA, or DHA significantly alters the fatty acid composition of CT-26 cells. Incorporation of these fatty acids resulted in decreased levels of monounsaturated fatty acids, while EPA and DHA also resulted in lower levels of AA. While significant elongation of both AA and EPA occurred, LIN remained relatively unmodified. Incorporation of radiolabeled fatty acids into different phospholipid species varied significantly. LIN was incorporated predominantly into phosphatidylcholine and had a much lower affinity for the ethanolamine phospholipids. DHA had a higher affinity for plasmenylethanolamine (1-O-alk-1'-enyl-2-acyl-sn-glycero-3-phosphoethanolamine) than the other fatty acids, while EPA had the highest affinity for phosphatidylethanol-amine (1,2-diacyl-sn-glycero-3-phosphoethanolamine). These results demonstrate that, in vitro, significant differences are seen between the various PUFA in CT-26 cells with respect to metabolism and distribution, and these may help to explain differences observed with respect to their effects on tumor growth and metastasis in the transplantable model

Calcium and vitamin D. Their potential roles in colon and breast cancer prevention.

Garland CF, Garland FC, Gorham ED.

Ann N Y Acad Sci. 1999; 889:107-19.

The geographic distribution of colon cancer is similar to the historical geographic distribution of rickets. The highest death rates from colon cancer occur in areas that had high prevalence rates of rickets--regions with winter ultraviolet radiation deficiency, generally due to a combination of high or moderately high latitude, high-sulfur content air pollution (acid haze), higher than average stratospheric ozone thickness, and persistently thick winter cloud cover. The geographic distribution of colon cancer mortality rates reveals significantly low death rates at low latitudes in the United States and significantly high rates in the industrialized Northeast. The Northeast has a combination of latitude, climate, and air pollution that prevents any synthesis of vitamin D during a five-month vitamin D winter. Breast cancer death rates in white women also rise with distance from the equator and are highest in areas with long vitamin D winters. Colon cancer incidence rates also have been shown to be inversely proportional to intake of calcium. These findings, which are consistent with laboratory results, indicate that most cases of colon cancer may be prevented with regular intake of calcium in the range of 1,800 mg per day, in a dietary context that includes 800 IU per day (20 micrograms) of vitamin D3. (In women, an intake of approximately 1,000 mg of calcium per 1,000 kcal of energy with 800 IU of vitamin D would be sufficient.) In observational studies, the source of approximately 90% of the calcium intake was vitamin D-fortified milk. Vitamin D may also be obtained from fatty fish. In addition to reduction of incidence and mortality rates from colon cancer, epidemiological data suggest that intake of 800 IU/day of vitamin D may be associated with enhanced survival rates among breast cancer cases

Effects of adenoviral gene transfer of C. elegans n-3 fatty acid desaturase on the lipid profile and growth of human breast cancer cells.

Ge Y, Chen Z, Kang ZB, et al.

Anticancer Res. 2002 Mar; 22(2A):537-43.

BACKGROUND: Current evidence from both experimental and human studies indicates that omega-6 polyunsaturated fatty acids (n-6 PUFAs) promote breast tumor development, whereas long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) exert suppressive effects. The ratio of n-6 to n-3 fatty acids appears to be an important factor in controlling tumor development. Human cells usually have a very high n-6/n-3 fatty acid ratio because they cannot convert n-6 PUFAs to n-3 PUFAs due to lack of an n-3 desaturase found in C. elegans. MATERIALS AND METHODS: Adenoviral strategies were used to introduce the C. elegans fat-1 gene encoding an n-3 fatty acid desaturase into human breast cancer cells followed by examination of the n-6/n-3 fatty acid ratio and growth of the cells. RESULTS: Infection of MCF-7 cells with an adenovirus carrying the fat-1 gene resulted in a high expression of the n-3 fatty acid desaturase. Lipid analysis indicated a remarkable increase in the levels of n-3 PUFAs accompanied with a large decrease in the contents of n-6 PUFAs, leading to a change of the n-6/n-3 ratio from 12.0 to 0.8. Accordingly, production of the eicosanoids derived from n-6 PUFA was reduced significantly in cells expressing the fat-1 gene. Importantly, the gene transfer induced mass cell death and inhibited cell proliferation. CONCLUSION: The gene transfer of the n-3 fatty acid desaturase, as a novel approach, can effectively modify the n-6/n-3 fatty acid ratio of human tumor cells and provide an anticancer effect, without the need of exogenous n-3 PUFA supplementation. These data also increase the understanding of the effects of n-3 fatty acids and the n-6/n-3 ratio on cancer prevention and treatment

Consumption of fish oil leads to prompt incorporation of eicosapentaenoic acid into colonic mucosa of patients prior to surgery for colorectal cancer, but has no detectable effect on epithelial cytokinetics.

Gee JM, Watson M, Matthew JA, et al.

J Nutr. 1999 Oct; 129(10):1862-5.

Fish oil (FO) was previously reported to partially normalize colorectal crypt cell cytokinetics in patients with colorectal neoplasms. We determined the effect of FO on the fatty acid composition of colonic mucosa and mesenteric adipose tissue and on rectal crypt cell proliferation in patients undergoing surgery for colonic carcinoma. Patients (49-28 males; 21 females) were randomly assigned to consume FO capsules (2 g b.d.; FO group) containing 1.4 g eicosapentaenoic acid (EPA) and 1.0 g docosahexaenoic acid per day, or safflower oil capsules (2 g b.d.; placebo group) for an average of 12.3 +/- 0.5 d prior to surgery. Rectal biopsies were obtained at entry, at surgery, and 8-12 wk postsurgery. Colonic biopsies and samples of mesenteric adipose tissue were analyzed for fatty acids by gas-liquid chromatography. Mitosis was determined in whole crypt mounts. The proportion of EPA (g/100 g total fatty acids) in mucosal lipids was significantly greater in FO patients compared to the placebo group, but there was no effect on mesenteric adipose tissue. However self-reported use of FO supplements prior to surgery was associated with higher levels of EPA in adipose tissue. There was no significant effect of FO on the frequency or spatial distribution of crypt cell mitosis. EPA from marine oil supplements is rapidly incorporated into the colonic mucosal lipids of humans, but the levels achieved in the present study did not modify colorectal cytokinetics

Meat, cooking methods and colorectal cancer: a case-referent study in Stockholm.

Gerhardsson d, V, Hagman U, Peters RK, et al.

Int J Cancer. 1991 Oct 21; 49(4):520-5.

The associations between methods of cooking meats and colorectal cancer were examined in a population-based case-referent study performed in Stockholm in 1986-1988. The study included 559 cases and 505 referents. Total meat intake, frequent consumption of brown gravy, and a preference for a heavily browned meat surface each independently increased the risk for colorectal cancer. The relative risks (RR) were higher for rectal than for colon cancer, and for boiled meat (RR colon = 1.7, RR rectum = 2.7) than for meat fried with a medium or lightly browned surface (RR colon = 0.8, RR rectum = 1.1), but the highest risks were for meat fried with a heavily browned surface (RR colon = 2.8, RR rectum = 6.0). The analyses were adjusted for year of birth, gender and fat intake. Further adjustments for total energy, dietary fiber intake, body mass and physical activity had little or no influence on the results. The findings suggest that, in addition to frequent meat intake, a heavily browned meat surface formed when frying meat at high temperatures is important in the etiology of colorectal cancer

Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis 4.

Giardiello FM, Hamilton SR, Krush AJ, et al.

N Engl J Med. 1993 May 6; 328(18):1313-6.

BACKGROUND. Familial adenomatous polyposis is an autosomal dominant disorder characterized by the formation of hundreds of colorectal adenomas and eventual colorectal cancer. Administration of the nonsteroidal antiinflammatory drug sulindac has been followed by regression of polyps in patients with this disorder, but no controlled trial of this drug in patients who have not had surgery has been reported. METHODS. We conducted a randomized, double-blind, placebo-controlled study of 22 patients with familial adenomatous polyposis, including 18 who had not undergone colectomy. The patients received sulindac at a dose of 150 mg orally twice a day for nine months or identical-appearing placebo tablets. The number and size of the polyps were evaluated every three months for one year. RESULTS. A statistically significant decrease in the mean number of polyps and their mean diameter occurred in patients treated with sulindac, as compared with those given placebo. When treatment was stopped at nine months, the number of polyps had decreased to 44 percent of base-line values and the diameter of the polyps to 35 percent of base-line values (P = 0.014 and P < 0.001, respectively, for the comparison with the changes in the group given placebo). No patient had complete resolution of polyps. Three months after treatment with sulindac was stopped, both the number and the size of the polyps increased in sulindac-treated patients but remained significantly lower than the values at base line. No side effects from sulindac were noted. CONCLUSIONS. Sulindac reduces the number and size of colorectal adenomas in patients with familial adenomatous polyposis, but its effect is incomplete, and it is unlikely to replace colectomy as primary therapy

Patterns of neoplastic spread in colorectal cancer: implications for surveillance CT studies.

Giess CS, Schwartz LH, Bach AM, et al.

AJR Am J Roentgenol. 1998 Apr; 170(4):987-91.

OBJECTIVE: This study was performed to assess patterns of metastatic disease shown on CT in colorectal cancer and to determine the diagnostic yield of routine pelvic CT in follow-up surveillance. MATERIALS AND METHODS: Pathology records and 3073 CT studies of 1119 patients with colorectal cancer were retrospectively reviewed. Primary tumor site, site of abdominal or pelvic metastases (liver, peritoneum, lymph nodes, local recurrence, or other), and incidental nonmetastatic pelvic disease were recorded. The superior iliac crests were considered the border between the abdomen (above) and the pelvis (below). RESULTS: Metastatic disease was present in 34% (1040/3073) of all CT studies: 33% (1007/3073) in the abdomen and 7% (227/3073) in the pelvis. Six percent (194/3073) of studies had metastases in both abdomen and pelvis. Forty-one percent (404/991) of studies showing abdominal primary colonic tumors showed metastatic disease: 40% (400/991) in the abdomen and 8% (78/991) in the pelvis. Four studies (0.4%; 4/991) in four different patients with abdominal primary colon tumors had isolated pelvic metastases; three of these were primary tumors of the cecum. Thirty-one percent (636/2082) of studies showing pelvic primary colonic tumors showed metastatic disease: 29% (607/2082) in the abdomen and 7% (149/2082) in the pelvis. Twenty-nine studies (1%; 29/2082) in 26 patients with pelvic primary colonic tumors revealed isolated pelvic metastases. CONCLUSION: In colorectal tumors arising within the abdomen, pelvic metastases are uncommon and isolated pelvic metastases are rare. Routine pelvic CT performed in the follow-up surveillance of patients with colorectal cancer with primary tumors arising in the abdominal portion of the colon has a low diagnostic yield

Physical activity, obesity, and risk of colorectal adenoma in women (United States).

Giovannucci E, Colditz GA, Stampfer MJ, et al.

Cancer Causes Control. 1996 Mar; 7(2):253-63.

The relationship between physical inactivity, body mass index (BMI) (wt[kg]/ht[m]2), and pattern of adipose distribution with risk of colorectal adenomas (precursors of cancer) was examined in 13,057 female nurses in the United States, 40 to 65 years of age in 1986, who had an endoscopy between 1986 and 1992. From 1986 to 1992, 439 participants were newly diagnosed with adenomas of the distal colorectum. After controlling for age, prior endoscopy, parental history of colorectal cancer, smoking, aspirin, and intakes of animal fat, dietary fiber, folate, methionine, and alcohol, physical activity was associated inversely with risk of large (> or = 1 cm) adenomas in the distal colon (relative risk [RR] = 0.57, 95 percent confidence interval [CI] = 0.30-1.08, comparing high and low quintiles of average weekly energy expenditure from leisure-time activities; P trend = 0.05). Much of the benefit came from activities of moderate intensity such as brisk walking. In addition, BMI was associated directly with risk of large adenomas in the distal colon (multivariate RR = 2.21 [CI = 1.18-4.16], P trend = 0.0001, for BMI > or = 29 cf < 21 kg/m2). Waist circumference and the waist-to-hip ratio (WHR) were not related significantly to adenoma independently of BMI, but women with both a high BMI and high WHR were at greater risk of large colon adenoma (multivariate RR = 1.99, CI = 0.98-4.05) than women with high BMI but relatively low WHR (multivariate RR = 1.35, CI = 0.61-2.97). BMI was not related to small (< 1 cm) adenoma risk but physical activity had an inverse association with small adenomas in the distal colon (multivariate RR = 0.68, CI = 0.40-1.15, P trend = 0.03). The relationships between BMI or physical activity were considerably weaker and inconsistent for rectal adenomas. These results, in women, support an inverse association between physical activity and occurrence or progression of adenomas in the distal colon; obesity is associated with an elevated risk of large adenomas

Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study.

Giovannucci E, Stampfer MJ, Colditz GA, et al.

Ann Intern Med. 1998 Oct 1; 129(7):517-24.

BACKGROUND: High intake of folate may reduce risk for colon cancer, but the dosage and duration relations and the impact of dietary compared with supplementary sources are not well understood. OBJECTIVE: To evaluate the relation between folate intake and incidence of colon cancer. DESIGN: Prospective cohort study. SETTING: 88,756 women from the Nurses' Health Study who were free of cancer in 1980 and provided updated assessments of diet, including multivitamin supplement use, from 1980 to 1994. PATIENTS: 442 women with new cases of colon cancer. MEASUREMENTS: Multivariate relative risk (RR) and 95% CIs for colon cancer in relation to energy-adjusted folate intake. RESULTS: Higher energy-adjusted folate intake in 1980 was related to a lower risk for colon cancer (RR, 0.69 [95% CI, 0.52 to 0.93] for intake > 400 microg/d compared with intake < or = 200 microg/d) after controlling for age; family history of colorectal cancer; aspirin use; smoking; body mass; physical activity; and intakes of red meat, alcohol, methionine, and fiber. When intake of vitamins A, C, D, and E and intake of calcium were also controlled for, results were similar. Women who used multivitamins containing folic acid had no benefit with respect to colon cancer after 4 years of use (RR, 1.02) and had only nonsignificant risk reductions after 5 to 9 (RR, 0.83) or 10 to 14 years of use (RR, 0.80). After 15 years of use, however, risk was markedly lower (RR, 0.25 [CI, 0.13 to 0.51]), representing 15 instead of 68 new cases of colon cancer per 10,000 women 55 to 69 years of age. Folate from dietary sources alone was related to a modest reduction in risk for colon cancer, and the benefit of long-term multivitamin use was present across all levels of dietary intakes. CONCLUSIONS: Long-term use of multivitamins may substantially reduce risk for colon cancer. This effect may be related to the folic acid contained in multivitamins

Epidemiologic studies of folate and colorectal neoplasia: a review.

Giovannucci E.

J Nutr. 2002 Aug; 132(8 Suppl):2350S-5S.

Dietary folate influences DNA methylation, synthesis and repair. Aberrations in these DNA processes may enhance carcinogenesis, particularly in rapidly proliferative tissues such as the colorectal mucosa. DNA methylation abnormalities may influence the expression of cancer-related genes, and inadequate levels of folate may lead to uracil misincorporation into DNA and to chromosomal breaks. Folate deficiency enhances intestinal carcinogenesis in several animal models. An increasing number of epidemiologic studies indicate that higher intakes of folate either from dietary sources or from supplements may lower the risk of colorectal adenoma and cancer. More limited data also suggest that dietary methionine, which might also influence methylation, may have a similar protective role. High alcohol consumption, which has a strong antifolate effect, also has been related to higher risk of colorectal neoplasia. The deleterious effects of alcohol are accentuated when folate or methionine intake is low. Some evidence also suggests that the risk of colorectal neoplasia may vary according to genetic polymorphisms in methylenetetrahydrofolate reductase, an enzyme that is involved in folate metabolism. The cumulative data indicate that maintaining adequate folate levels may be important in lowering risk of colorectal cancer

Methylenetetrahydrofolate reductase, alcohol dehydrogenase, diet, and risk of colorectal adenomas.

Giovannucci E, Chen J, Smith-Warner SA, et al.

Cancer Epidemiol Biomarkers Prev. 2003 Oct; 12(10):970-9.

An increased occurrence of colorectal cancer and its adenoma precursor is observed among individuals with low intakes or circulating levels of folate, especially if alcohol intake is high, although results have not been statistically significant in all studies. We examined folate and alcohol intake and genetic polymorphisms in methylenetetrahydrofolate reductase [MTHFR 667-->T (ala-->val) and MTHFR 1298A-->C (gln-->ala)] (associated with reduced MTHFR activity) and in alcohol dehydrogenase 3 [ADH3 (2-2) associated with decreased alcohol catabolism] in relation to risk of colorectal adenoma in the Health Professionals Follow-Up Study. Among 379 cases and 726 controls, MTHFR genotypes were not appreciably related to risk of adenoma, but a suggestive interaction (P = 0.09) was observed between MTHFR 677C-->T and alcohol intake; men with TT homozygotes who consumed 30+ g/day of alcohol had an odds ratio (OR) of 3.52 [95% confidence interval (CI), 1.41-8.78] relative to drinkers of < or =5 g/day with the CC/CT genotypes. ADH3 genotype alone was not appreciably related to risk, but its influence was modified by alcohol intake. Compared with fast alcohol catabolizers [ADH3(1-1)] with low intakes of alcohol (< or =5 g/day), high consumers of alcohol (30+ g/day) had a marked increase in risk if they had the genotype associated with slow catabolism [ADH3(2-2); OR, 2.94; 95% CI, 1.24-6.92] or intermediate catabolism [ADH3(1-2)] of alcohol (OR, 1.83; 95% CI, 1.03-3.26) but not if they were fast catabolizers [ADH3(1-1); OR = 1.27; 95% CI = 0.63-2.53). In addition, an increased risk of colorectal adenoma (OR, 17.1; 95% CI, 2.1-137) was observed for those with the ADH3(2-2) genotype and high alcohol-low folate intake compared with those with low alcohol-high folate intake and the ADH3(1-1) genotype (P for interaction = 0.006). Our results indicate that high intake of alcohol is associated with an increased risk of colorectal adenoma, particularly among MTHFR 677TT and ADH3(2-2) homozygotes. The findings that alcohol interacts with a folate-related gene (MTHFR) and that the interaction between alcohol and ADH3 is stronger among those with low folate intake support the hypothesis that the carcinogenic influence of alcohol in the large bowel is mediated through folate status

Effects of colonic lumenal components on AP-1-dependent gene transcription in cultured human colon carcinoma cells 3.

Glinghammar B, Holmberg K, Rafter J.

Carcinogenesis. 1999 Jun; 20(6):969-76.

We recently suggested that prolonged deregulated expression of AP-1 activity in colonic cells by bile acids may contribute to tumour promotion in the colon. In the present study, using two human colon carcinoma cell lines, HT-29 and HCT 116, transiently transfected with the AP-1-luciferase reporter construct, we showed that the bile acids, deoxycholate, chenodeoxycholate, ursodeoxycholate and lithocholate, induced AP-1-dependent gene transcription in a dose-dependent manner, whereas cholate was without effect. The greatest effect was observed with deoxycholate, and the ability of this bile acid to induce reporter gene activity was significantly correlated with its ability to induce cell proliferation (r = 0.91, P = 0.01). Cholesterol and the long chain fatty acids, myristate, palmitate and stearate, had no effect on AP-1-dependent gene transcription, whereas the short chain fatty acid, butyrate, exhibited a marked effect. Mindful of the fact that the concentrations of lumenal components that are actually in or entering the epithelial cells in the colon are presumably lower than lumenal values, we considered it of interest to determine the effect of dilution on the capacity of human faecal water to induce AP-1 activity and also cell proliferation. We demonstrated that diluted lipid extracts, from all of the faecal water samples examined, significantly induced AP-1-dependent gene transcription in the colonic cells, and that this effect differed markedly between the extracts. We confirmed that the faecal water lipid extracts, at the same dilution at which they increased AP-1 activity, significantly induced proliferation in the same cell line. These data suggest that lipid components of human faecal water, which is in direct contact with the colon epithelium and may be physiologically more active than the solid phase, can activate AP-1, a transcription factor whose activation has been associated with the promotion of neoplastic transformation

The effect of dietary omega-3 polyunsaturated fatty acids on T-lymphocyte subsets of patients with solid tumors.

Gogos CA, Ginopoulos P, Zoumbos NC, et al.

Cancer Detect Prev. 1995; 19(5):415-7.

The effect of omega-3 polyunsaturated fatty acids (PUFA) on the immune system seems to be beneficial. There has been a number of studies concerning the effect of dietary omega-3 PUFA on different immune parameters. The aim of our present study was to investigate the effect of dietary omega-3 PUFA on T-cell subsets and natural killer (NK) cells of patients with solid tumors. We studied 20 patients with solid tumors who received 18 g fish oil/day for 40 consecutive days. We detected a significant increase in T-helper/T-suppressor cell ratio 40 days into omega-3 supplementation, due mainly to a decrease in the number of suppressor T cells. We concluded that dietary omega-3 fatty acids may have a beneficial effect on the already compromised immune system of patients suffering from solid tumors

Dietary omega-3 polyunsaturated fatty acids plus vitamin E restore immunodeficiency and prolong survival for severely ill patients with generalized malignancy: a randomized control trial.

Gogos CA, Ginopoulos P, Salsa B, et al.

Cancer. 1998 Jan 15; 82(2):395-402.

BACKGROUND. The aim of the current prospective, randomized control study was to investigate the effect of dietary omega-3 polyunsaturated fatty acids plus vitamin E on the immune status and survival of well-nourished and malnourished patients with generalized malignancy. METHODS. Sixty patients with generalized solid tumors were randomized to receive dietary supplementation with either fish oil (18 g of omega-3 polyunsaturated fatty acids, PUFA) or placebo daily until death. Each group included 15 well-nourished and 15 malnourished patients. The authors measured total T cells, T-helper cells, T-suppressor cells, natural killer cells, and the synthesis of interleukin-1, interleukin-6, and tumor necrosis factor by peripheral blood mononuclear cells before and on Day 40 of fish oil supplementation. Karnofsky performance status, nutritional state, and survival were also estimated. RESULTS. The ratio of T-helper cells to T-suppressor cells was significantly lower in malnourished patients. Omega-3 PUFA had a considerable immunomodulating effect by increasing this ratio in the subgroup of malnourished patients. There were no significant differences in cytokine production among the various groups, except for a decrease in tumor necrosis factor production in malnourished cancer patients, which was restored by omega-3 fatty acids. The mean survival was significantly higher for the subgroup of well-nourished patients in both groups, whereas omega-3 fatty acids prolonged the survival of all the patients. CONCLUSIONS. Malnutrition appears to be an important predictor of survival for patients with end stage malignant disease. Omega-3 polyunsaturated fatty acids had a significant immunomodulating effect and seemed to prolong the survival of malnourished patients with generalized malignancy

A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer.

Goldberg RM, Sargent DJ, Morton RF, et al.

J Clin Oncol. 2004 Jan 1; 22(1):23-30.

PURPOSE: Three agents with differing mechanisms of action are available for treatment of advanced colorectal cancer: fluorouracil, irinotecan, and oxaliplatin. In this study, we compared the activity and toxicity of three different two-drug combinations in patients with metastatic colorectal cancer who had not been treated previously for advanced disease. PATIENTS AND METHODS: Patients were concurrently randomly assigned to receive irinotecan and bolus fluorouracil plus leucovorin (IFL, control combination), oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX), or irinotecan and oxaliplatin (IROX). The primary end point was time to progression, with secondary end points of response rate, survival time, and toxicity. RESULTS: A total of 795 patients were randomly assigned between May 1999 and April 2001. A median time to progression of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15.0 months, respectively) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for time to progression and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin. CONCLUSION: The FOLFOX regimen of oxaliplatin and infused fluorouracil plus leucovorin was active and comparatively safe. It should be considered as a standard therapy for patients with advanced colorectal cancer

Vitamin D, calcium supplementation, and colorectal adenomas: results of a randomized trial.

Grau MV, Baron JA, Sandler RS, et al.

J Natl Cancer Inst. 2003 Dec 3; 95(23):1765-71.

BACKGROUND: Calcium and vitamin D both appear to have antineoplastic effects in the large bowel. Although these nutrients are inter-related metabolically in bone and in the normal intestine, their potential interactions in large-bowel carcinogenesis are not well understood. METHODS: We assessed independent and joint effects of calcium supplementation and vitamin D status on adenoma recurrence in 803 subjects in a multi-center, placebo-controlled randomized clinical trial of calcium supplementation for the prevention of colorectal adenoma recurrence. Serum levels of 25-hydroxy [25-(OH)] vitamin D and 1,25-dihydroxy [1,25-(OH)2] vitamin D levels were determined, and the Taq I and Fok I polymorphisms in the vitamin D receptor (VDR) gene were analyzed by polymerase chain reaction. Risk ratios (RRs) for any adenoma recurrence were computed for calcium supplementation within groups defined by serum vitamin D levels and for serum vitamin D levels within treatment groups. Associations of VDR polymorphisms with recurrence risk were also evaluated. All statistical tests were two-sided. RESULTS: Among subjects with baseline 25-(OH) vitamin D levels at or below the median (29.1 ng/mL), calcium supplementation was not associated with adenoma recurrence, whereas among those with levels above the median, calcium supplementation was associated with a reduced risk (RR = 0.71, 95 % confidence interval [CI] = 0.57 to 0.89, P for interaction =.012). Conversely, serum 25-(OH) vitamin D levels were associated with a reduced risk only among subjects receiving calcium supplements (RR per 12 ng/mL increase of vitamin D = 0.88, 95% CI = 0.77 to 0.99, P for interaction =.006). VDR polymorphisms were not related to adenoma recurrence and did not modify the associations with vitamin D or calcium. CONCLUSIONS: Calcium supplementation and vitamin D status appear to act largely together, not separately, to reduce the risk of colorectal adenoma recurrence. VDR genotype does not appear to be associated with risk

Cancer statistics, 2000.

Greenlee RT, Murray T, Bolden S, et al.

CA Cancer J Clin. 2000 Jan; 50(1):7-33.

The Surveillance Research Program of the American Cancer Society's Department of Epidemiology and Surveillance Research reports its annual compilation of estimated cancer incidence, mortality, and survival data for the United States in the year 2000. After 70 years of increases, the recorded number of total cancer deaths among men in the US declined for the first time from 1996 to 1997. This decrease in overall male mortality is the result of recent down-turns in lung and bronchus cancer deaths, prostate cancer deaths, and colon and rectum cancer deaths. Despite decreasing numbers of deaths from female breast cancer and colon and rectum cancer, mortality associated with lung and bronchus cancer among women continues to increase. Lung cancer is expected to account for 25% of all female cancer deaths in 2000. This report also includes a summary of global cancer mortality rates using data from the World Health Organization

Dietary fiber and colon cancer.

Greenwald P, Lanza E.

Bol Asoc Med P R. 1986 Jul; 78(7):311-3.

CEA, TPS, CA 19-9 and CA 72-4 and the fecal occult blood test in the preoperative diagnosis and follow-up after resective surgery of colorectal cancer.

Griesenberg D, Nurnberg R, Bahlo M, et al.

Anticancer Res. 1999 Jul; 19(4A):2443-50.

In a prospective clinical study we examined the diagnostic procedures used in the preoperative diagnosis of colorectal cancer patients (n = 176) and the value of supplementation of standard diagnostic methods (clinical investigation, colonoscopy, barium enema, ultrasound, computer tomography) with a test for occult fecal blood (FOBT) and an expanded tumor marker panel (CA 19-9, TPS and CA 72-4 in addition to CEA) in the postoperative follow-up (n = 116, mean follow-up 21 months). Preoperative diagnosis based on colonoscopy/barium enema, followed by histology and the imaging methods, in most cases US and/or CT. Patients with postoperative stage Dukes D and after palliative surgery were excluded from the follow-up study (n = 43). The patients were seen every three months (clinical investigation, US, CT, tumor markers, FOBT) within the first two postoperative years and every half a year thereafter. 83 of the 116 patients (16%) developed a recurrent disease and 5 of them could be reoperated with curative intention. In addition to the 19 patients 14 simultaneously admitted patients with recurrence of colorectal cancer (total n = 33) were studied. The results of our study analyzing the sensitivity and specificity of colonoscopy, tumor, markers and the FOBT in the preoperative and postoperative phases as well as in the diagnosis of recurrent disease of colorectal cancer confirms the view that FOBT and tumor markers cannot replace endoscopic and imaging methods. However they support the concept, that diagnosis and follow-up of colorectal cancer should be based on a combination of clinical investigation and imaging methods (US, CT etc. and endoscopic and/or x-ray examination) with supplementation by FOBT and determination of tumor markers, mainly CEA. In the case a patient is asking for prognostic and recurrence information as early and as valid as possible we currently recommend the following procedure for the first two years after surgery: every three months the determination of tumor markers, FOBT as well as ultrasound of the upper abdomen and CT of the lower abdomen and every half year a total colonoscopy. The question of whether this program will also have a therapeutical relevance depends on several factors like the personal experience and concepts of the consulting surgeons and oncologists and also on the tasks and duties which are considered worthy by the patient for his further life if confronted with the diagnosis of recurrent colorectal cancer

Regulatory potential of n-3 fatty acids in immunological and inflammatory processes.

Grimm H, Mayer K, Mayser P, et al.

Br J Nutr. 2002 Jan; 87 Suppl 1:S59-S67.

Over the last few years immunonutrition has gained increasing importance. Among other compounds lipids, especially n-3 polyunsaturated fatty acids, were shown to influence the immune response. The anti-inflammatory effects they exert can be induced by free fatty acids, triglyceride fatty acids, after incorporation into the membrane phopspholipid bilayer or following metabolism to eicosanoids. n-3 Fatty acids influence inflammatory cell activation processes from signal transduction to protein expression even involving effects at the genomic level. n-3 Fatty acid-mediated mechanisms decreased cytokine-induced adhesion molecule expression, thereby reducing inflammatory leucocyte-endothelium interactions and modified lipid mediator synthesis, thus influencing the transendothelial migration of leucocytes and leucocyte trafficking in general. Even the metabolic repertoire of specific immunocompetent cells such as cytokine release or proliferation is modified by n-3 fatty acids. Beyond this they regulate lipid homeostasis shifting the metabolic pathways towards energy supply thus optimizing the function of immune cells. Due to the regulatory impact on different processes of inflammatory and immune cell activation n-3 fatty acids provide positive effects on various states of immune deficiencies and diseases with a hyperinflammatory character, among which selected examples are presented

Colonoscopic screening of persons with suspected risk factors for colon cancer. I. Family history.

Grossman S, Milos ML.

Gastroenterology. 1988 Feb; 94(2):395-400.

A family history of colorectal cancer is believed to place persons at increased risk for development of the disease. It is unclear, however, how "strong" a family history must be to increase this risk or to make colonoscopic screening appropriate. We performed initial colonoscopy in 154 asymptomatic subjects whose only suspected risk factor was one or two first-degree relatives with colorectal cancer; 48 of these subjects also had affected second- and third-degree relatives. We found 45 adenomas in 28 subjects (18%). One subject had a 3-cm villous adenoma. In 6 subjects, the most advanced findings were tubular adenomas 5-9 mm in diameter; in 21 subjects, we found only tubular adenomas that were 2-4 mm in diameter. The prevalence of adenomas increased significantly with age of subjects (p less than 0.01). Although the overall prevalence of colorectal neoplasms in our group was no greater than might be expected in the general population, subjects with two first-degree relatives tended to have more diminutive adenomas than those with one such relative. Our findings suggest that colonoscopy is not an appropriate first step in screening persons with one affected first-degree relative. For those with more complex family histories, more data are needed--particularly on the prevalence of advanced neoplasms--to determine whether a screening technique that is less costly and less invasive than colonoscopy may be adequate

Molecular mechanisms of anti-angiogenic effect of curcumin.

Gururaj AE, Belakavadi M, Venkatesh DA, et al.

Biochem Biophys Res Commun. 2002 Oct 4; 297(4):934-42.

Modulation of pathological angiogenesis by curcumin (diferuloylmethane), the active principle of turmeric, seems to be an important possibility meriting mechanistic investigations. In this report, we have studied the effect of curcumin on the growth of Ehrlich ascites tumor cells and endothelial cells in vitro. Further, regulation of tumor angiogenesis by modulation of angiogenic ligands and their receptor gene expression in tumor and endothelial cells, respectively, by curcumin was investigated. Curcumin, when injected intraperitoneally (i.p) into mice, effectively decreased the formation of ascites fluid by 66% in EAT bearing mice in vivo. Reduction in the number of EAT cells and human umbelical vein endothelial cells (HUVECs) in vitro by curcumin, without being cytotoxic to these cells, is attributed to induction of apoptosis by curcumin, as is evident by an increase in cells with fractional DNA content seen in our results on FACS analysis. However, curcumin had no effect on the growth of NIH3T3 cells. Curcumin proved to be a potent angioinhibitory compound, as demonstrated by inhibition of angiogenesis in two in vivo angiogenesis assay systems, viz. peritoneal angiogenesis and chorioallantoic membrane assay. The angioinhibitory effect of curcumin in vivo was corroborated by the results on down-regulation of the expression of proangiogenic genes, in EAT, NIH3T3, and endothelial cells by curcumin. Our results on Northern blot analysis clearly indicated a time-dependent (0-24h) inhibition by curcumin of VEGF, angiopoietin 1 and 2 gene expression in EAT cells, VEGF and angiopoietin 1 gene expression in NIH3T3 cells, and KDR gene expression in HUVECs. Further, decreased VEGF levels in conditioned media from cells treated with various doses of curcumin (1 microM-1mM) for various time periods (0-24h) confirm its angioinhibitory action at the level of gene expression. Because of its non-toxic nature, curcumin could be further developed to treat chronic diseases that are associated with extensive neovascularization

Colon cancer screening practices after genetic counseling and testing for hereditary nonpolyposis colorectal cancer.

Hadley DW, Jenkins JF, Dimond E, et al.

J Clin Oncol. 2004 Jan 1; 22(1):39-44.

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common hereditary form of colon cancer. Cancer screening recommendations differ between individuals identified to carry an HNPCC mutation and those who do not carry a known family mutation. We assessed the impact of genetic counseling and testing (GCT) on the use of endoscopic screening procedures and adherence to recommended endoscopic screening guidelines in 56 asymptomatic at-risk individuals from families known to carry an HNPCC mutation. PATIENTS AND METHODS: We analyzed data on colonoscopy and flexible sigmoidoscopy screenings collected before GCT and 6 months and 12 months post-GCT on 17 mutation-positive and 39 true mutation-negative individuals. Main outcome measures were use of endoscopic screening and adherence to recommended guidelines for the relevant mutation status. Mutation status, age, sex, employment, and income were analyzed as predictor variables. RESULTS: Among mutation-negative individuals, use of colonoscopy and flexible sigmoidoscopy decreased significantly between pre- and post-GCT (P <.00001 and P <.0003, respectively). Among mutation-positive individuals, a nonsignificant increase (P =.24) in use was noted. Age was also associated with use of endoscopic screening after GCT (P =.03). Mutation status (odds ratio [OR], 7.5; P =.02) and employment (OR, 8.6; P =.025) were associated with nonadherence to endoscopic screening guidelines. More mutation-negative individuals strictly adhered to guidelines than did mutation-positive individuals (87% v 65%). CONCLUSION: Genetic counseling and testing for HNPCC significantly influences the use of colonic endoscopy and adherence to recommendations for colon cancer screening

Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic dosing and its antiangiogenic basis.

Hahnfeldt P, Folkman J, Hlatky L.

J Theor Biol. 2003 Feb 21; 220(4):545-54.

The general utility of the maximum tolerated dose (MTD) paradigm, a strategy aimed at optimizing the chance of total tumor cell eradication, is here questioned. Evidence to date suggests that for many tumors the potential for eradication is in fact remote, with patients consistently demonstrating tumor cell presence subsequent to MTD treatments having eradicative intent. The failure to eradicate is attributed largely to the heterogeneous nature of the tumor. Heterogeneous cell populations demonstrate short-term refractoriness to up-front dose delivery, but "resensitize" as part of dose recovery, showing increased overall susceptibility to a given series of doses when delivered more evenly spaced. It is demonstrated: (1) that the minimization of total tumor burden, rather than complete eradication, may often be the more practical objective; and (2) that regularly spaced, "metronomic" dosing is the best way to achieve it. As a corollary, it is found that the more efficient ability of the tumor endothelial cells to resensitize following dosing predicts a targeting bias towards the endothelial compartment of a tumor when metronomic dosing is employed. This lends theoretical support to recent empirical studies showing that regularly spaced dosing schedules with no extended rest periods act more antiangiogenically, thereby delaying or avoiding the onset of acquired resistance

Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice.

Hanahan D, Bergers G, Bergsland E.

J Clin Invest. 2000 Apr; 105(8):1045-7.

The angiogenic switch for vascular endothelial growth factor (VEGF)-A, VEGF-B, VEGF-C, and VEGF-D in the adenoma-carcinoma sequence during colorectal cancer progression.

Hanrahan V, Currie MJ, Gunningham SP, et al.

J Pathol. 2003 Jun; 200(2):183-94.

Angiogenesis is essential for tumour growth and metastasis. It is controlled by angiogenic factors, one of the most important being vascular endothelial growth factor (VEGF)-A. Although its role has been demonstrated in many tumour types including colorectal carcinoma (CRC), the importance of the newer family members in adenoma, invasive tumour growth, and progression to a metastatic phenotype has been poorly characterized in CRC. The aim of this study was to determine the role and timing of the VEGF angiogenic switch during CRC progression. We measured the gene expression of VEGF ligands (VEGF-A, VEGF-B, VEGF-C, and VEGF-D) and their receptors (VEGFR-1, VEGFR-2, and VEGFR-3), in normal colorectal tissues (n = 20), adenomas (n = 10), and in CRC (n = 71) representing different Duke's stages using ribonuclease protection assay, semi-quantitative relative reverse transcriptase polymerase chain reaction, together with the pattern of their expression by immunohistochemistry. VEGF-A mRNA was the most abundant in colorectal tissue, followed by VEGF-B, VEGF-C, and VEGF-D. VEGF-A and VEGF-B mRNAs were significantly more abundant in adenomas (p = 0.0003 and p = 0.04 respectively) compared with normal tissues, while VEGF-A and VEGF-C were significantly increased in carcinomas compared with normal tissues (p = 0.0006 and p = 0.0009 respectively). A significantly greater amount of VEGF-C mRNA was present in carcinomas compared with adenomas (p = 0.03), whereas there was a significant reduction of VEGF-B in carcinomas compared with adenomas (p = 0.0002). VEGF-D mRNA was significantly more abundant in normal tissues than in adenomas (p = 0.0001) and carcinomas (p < 0.0001). In normal tissues distant from the primary tumour, there was a significantly greater amount of VEGF-A and VEGF-D mRNA in patients with Duke's B and Duke's C respectively, compared with Duke's A stage tumours (p = 0.04 and p = 0.01 respectively). Immunohistochemistry showed low basal levels of all ligands in histologically normal tissues and their expression in the epithelium of tumours reflected the levels of mRNA expression identified. VEGF-A and VEGF-C mRNA levels correlated significantly with tumour grade (p = 0.01 and p = 0.01 respectively) and tumour size (p = 0.001 and p = 0.01 respectively), but not with patient age, sex, presence of infiltrative margin, lymphocytic response, vascular invasion, Duke's stage, or lymph node involvement (p > 0.05). VEGF-B mRNA correlated with an infiltrative margin (p = 0.04) but no other clinicopathological variable, and expression of VEGF-D demonstrated no association with any parameter examined. VEGFR-1 was significantly correlated with tumour grade (p = 0.02), Duke's stage (p < 0.001), and lymph node involvement (p = 0.004), VEGFR-2 with lymph node involvement (p = 0.02), and VEGFR-3 did not correlate with any of the clinicopathological variables tested. These results suggest that VEGF-A and VEGF-B play a role early in tumour development at the stage of adenoma formation and that VEGF-C plays a role in advanced disease when there is more likelihood of metastatic spread. The finding of increased levels of VEGF-A and VEGF-D expression in normal tissues collected from a site distant from the primary tumour indicates changes in the surrounding tumour environment that may enhance the subsequent spread of tumour cells

Prevention of alterations in postoperative lymphocyte subpopulations by cimetidine and ibuprofen.

Hansbrough JF, Zapata-Sirvent RL, Bender EM.

Am J Surg. 1986 Feb; 151(2):249-55.

Surgical procedures probably result in a temporary state of immunosuppression. Identification of functional lymphocyte subclasses using appropriate monoclonal antibodies appears to serve as a sensitive, accurate, and reproducible measure of immune status in patients in many disease states. Using monoclonal antibodies specific for lymphocyte surface markers and immunofluorescent assay, we quantitated lymphocyte subpopulations in patients undergoing surgical procedures. Cholecystectomy, colon surgery, and coronary bypass procedures all resulted in postoperative decreases in helper and inducer populations and increases in cytotoxic suppressor populations, with resultant depressions in the helper to suppressor lymphocyte ratio. Studies in an additional group of patients who underwent cholecystectomy demonstrated that these changes could be prevented by perioperative administration of ibuprofen and cimetidine. These results suggest that prostaglandins and histamines are involved in immunoregulatory events after major operation. The ability of specific pharmacologic therapy to prevent alterations in lymphocyte populations suggest that postoperative immunity may be preserved, hopefully leading to greater host resistance against infection and tumor dissemination

Effects of daily oral administration of quercetin chalcone and modified citrus pectin on implanted colon-25 tumor growth in Balb-c mice.

Hayashi A, Gillen AC, Lott JR.

Altern Med Rev. 2000 Dec; 5(6):546-52.

The health benefits of fruits and vegetables have been the subject of numerous investigations over many years. Two natural substances, quercetin (a flavonoid) and citrus pectin (a polysaccharide found in the cell wall of plants) are of particular interest to cancer researchers. Two modified versions of these substances - quercetin chalcone (QC) and a pH-modified citrus pectin (MCP) - are the focus of this study. Previous research has confirmed that quercetin exhibits antitumor properties, likely due to immune stimulation, free radical scavenging, alteration of the mitotic cycle in tumor cells, gene expression modification, anti-angiogenesis activity, or apoptosis induction, or a combination of these effects. MCP has inhibited metastases in animal studies of prostate cancer and melanoma. To date, no study has demonstrated a reduction in solid tumor growth with MCP, and there is no research into the antitumor effect of QC. This study examines the effects of MCP and QC on the size and weight of colon-25 tumors implanted in balb-c mice. Fifty mice were orally administered either 1 ml distilled water (controls), low-dose QC (0.8 mg/ml), high-dose QC (1.6 mg/ml), low-dose MCP (0. 8 mg/ml) or high-dose MCP (1.6 mg/ml) on a daily basis, beginning the first day of tumor palpation (usually eight days post-implantation). A significant reduction in tumor size was noted at day 20 in all groups compared to controls. The groups given low-dose QC and MCP had a 29-percent (NS) and 38-percent (p<0.02) decrease in size, respectively. The high-dose groups had an even more impressive reduction in size; 65 percent in the QC group and 70 percent in the mice given MCP (both p<0.001). This is the first evidence that MCP can reduce the growth of solid primary tumors, and the first research showing QC has antitumor activity. Additional research on these substances and their effect on human cancers is warranted

Growth and recurrence of colorectal polyps: a double-blind 3-year intervention with calcium and antioxidants.

Hofstad B, Almendingen K, Vatn M, et al.

Digestion. 1998; 59(2):148-56.

BACKGROUND: Dietary calcium and antioxidants have been suggested as protective agents against colorectal cancer. This has been supported by animal experimental studies, case control and cohort studies. MATERIALS AND METHODS: In a prospective intervention study of colorectal adenomas, and intermediary stage in colorectal carcinogenesis, 116 polyp-bearing patients received a placebo-controlled daily mixture of beta-carotene 15 mg, vitamin C 150 mg, vitamin E 75 mg, selenium 101 microg, and calcium (1.6 g daily) as carbonate for a period of 3 years with annual colonoscopic follow-up to test if the mixture was able to reduce polyp growth or recurrence. All polyps of < 10 mm at enrollment or follow-up were left unresected until the end of the study. RESULTS: 87-91% of the patients attended the annual endoscopic follow-up investigations, and 19% of the patients dropped out of the medical intervention. The rest consumed 85% of the total amount of tablets over the 3 years. The fecal calcium concentration was 2.3-2.7 times higher in patients taking active medication compared to the placebo group. Diet registration showed that, when adding the intake of antioxidants and calcium from diet and intervention, there was a significant difference between the intake of these substances in the active and the placebo group. No difference was detected in the growth of adenomas between the active and the placebo group from year to year and for the total study period. Moreover, there was no effect on polyps of < 5 or 5-9 mm, or on polyps in the different colonic segments analyzed separately. A reduced growth of adenomas was found in patients <60 years of age taking active medication (n = 8) compared to those taking placebo (n = 6; mean difference 2.3 mm; 95% CI 0.26-4.36). There was a significantly lower number of patients free of new adenomas in the placebo group compared to those taking active medication as tested by logistic regression and Kaplan-Meier analysis (log-rank test p value 0.035). Subgroup analysis showed that only the group of patients with no family history of colorectal cancer, those with only one adenoma at inclusion, and those <65 years benefitted from the intervention medication. CONCLUSION: The study did not find an overall effect on polyp growth. Our data, however, may support a protective role of calcium and antioxidants on new adenoma formation

Effects of purified green and black tea polyphenols on cyclooxygenase- and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues.

Hong J, Smith TJ, Ho CT, et al.

Biochem Pharmacol. 2001 Nov 1; 62(9):1175-83.

The effects of green and black tea polyphenols on cyclooxygenase (COX)- and lipoxygenase (LOX)-dependent arachidonic acid metabolism in normal human colon mucosa and colon cancers were investigated. At a concentration of 30 microg/mL, (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), and (-)-epicatechin-3-gallate (ECG) from green tea and theaflavins from black tea inhibited LOX-dependent activity by 30-75%. The formation of 5-, 12-, and 15-LOX metabolites was inhibited to a similar extent. Tea polyphenols also inhibited COX-dependent arachidonic acid metabolism in microsomes from normal colon mucosa, with ECG showing the strongest inhibition. The formation of thromboxane (TBX) and 12-hydroxyheptadecatrienoic acid (HHT) was decreased to a greater extent than other metabolites. The inhibitory effects of tea polyphenols on COX activity, however, were less pronounced in tumor microsomes than in normal colon mucosal microsomes. Theaflavins strongly inhibited the formation of TBX and HHT, but increased the production of prostaglandin E(2) (PGE(2)) in tumor microsomes. The enhancing effect of theaflavins on PGE(2) production was related to the COX-2 level in the microsomes. Although theaflavin inhibited ovine COX-2, its activity in the formation of PGE(2) was stimulated by theaflavin when ovine COX-2 was mixed with microsomes, suggesting that theaflavin affects the interaction of COX-2 with other microsomal factors (e.g. PGE synthase). The present results indicate that tea polyphenols can affect arachidonic acid metabolism in human colon mucosa and colon tumors, and this action may alter the risk for colon cancer in humans

Oncogenic ras induces gastrin/CCKB receptor gene expression in human colon cancer cell lines LoVo and Colo320HSR.

Hori H, Nakata H, Iguchi G, et al.

J Lab Clin Med. 2003 May; 141(5):335-41.

Gastrin has the ability to stimulate cell growth in some colorectal cancer cells and some of these cells also express gastrin/CCKB receptors, suggesting that gastrin and its autocrine loop are involved in their proliferation. We previously reported that oncogenic ras induced gastrin gene expression in colon cancer cells. The aim of this study was to investigate whether oncogenic ras also induces gastrin/CCKB receptor gene expression. A transiently transfected activated ras vector stimulated gastrin/CCKB receptor transcriptional activities in both Colo320HSR and LoVo cells, but these ras-increased activities were inhibited by a specific MEK inhibitor, PD98059. An RPA demonstrated that activated ras increased endogenous gastrin/CCKB receptor mRNA levels and PD98059 decreased them in LoVo cells. These findings suggest that oncogenic ras induces gastrin/CCKB receptor gene expression through some intracellular signaling pathways, including MEK, in colon cancer cell lines

Dietary intake of fiber and decreased risk of cancers of the colon and rectum: evidence from the combined analysis of 13 case-control studies.

Howe GR, Benito E, Castelleto R, et al.

J Natl Cancer Inst. 1992 Dec 16; 84(24):1887-96.

BACKGROUND: Colorectal cancer is a major public health problem in both North America and western Europe, and incidence and mortality rates are rapidly increasing in many previously low-risk countries. It has been hypothesized that increased intakes of fiber, vitamin C, and beta carotene could decrease the risk of colorectal cancer. PURPOSE: The objective of this study was to examine the effects of fiber, vitamin C, and beta-carotene intakes on colorectal cancer risk in a combined analysis of data from 13 case-control studies previously conducted in populations with differing colorectal cancer rates and dietary practices. The study was designed to estimate risks in the pooled data, to test the consistency of the associations across the studies, and to examine interactions of the effects of the nutrients with cancer site, sex, and age. METHODS: Original data records for 5287 case subjects with colorectal cancer and 10,470 control subjects without disease were combined. Logistic regression analysis was used to estimate relative risks and confidence intervals for intakes of fiber, vitamin C, and beta carotene, with the effects of study, sex, and age group being adjusted by stratification. RESULTS: Risk decreased as fiber intake increased; relative risks were 0.79, 0.69, 0.63, and 0.53 for the four highest quintiles of intake compared with the lowest quintile (trend, P < .0001). The inverse association with fiber is seen in 12 of the 13 studies and is similar in magnitude for left- and right-sided colon and rectal cancers, for men and for women, and for different age groups. In contrast, after adjustment for fiber intake, only weak inverse associations are seen for the intakes of vitamin C and beta carotene. CONCLUSION: This analysis provides substantive evidence that intake of fiber-rich foods is inversely related to risk of cancers of both the colon and rectum. IMPLICATIONS: If causality is assumed, we estimate that risk of colorectal cancer in the U.S. population could be reduced about 31% (50,000 cases annually) by an average increase in fiber intake from food sources of about 13 g/d, corresponding to an average increase of about 70%

Inhibitory effects of curcumin on in vitro lipoxygenase and cyclooxygenase activities in mouse epidermis.

Huang MT, Lysz T, Ferraro T, et al.

Cancer Res. 1991 Feb 1; 51(3):813-9.

Topical application of curcumin, the yellow pigment in turmeric and curry, strongly inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase activity, DNA synthesis, and tumor promotion in mouse skin (Huang et al., Cancer Res., 48: 5941-5946, 1988). Chlorogenic acid, caffeic acid, and ferulic acid (structurally related dietary compounds) were considerably less active. In the present study, topical application of curcumin markedly inhibited TPA- and arachidonic acid-induced epidermal inflammation (ear edema) in mice, but chlorogenic acid, caffeic acid, and ferulic acid were only weakly active or inactive. The in vitro addition of 3, 10, 30, or 100 microM curcumin to cytosol from homogenates of mouse epidermis inhibited the metabolism of arachidonic acid to 5-hydroxyeicosatetraenoic acid (5-HETE) by 40, 60, 66, or 83%, respectively, and the metabolism of arachidonic acid to 8-HETE was inhibited by 40, 51, 77, or 85%, respectively [IC50 (concentration needed for 50% inhibition) = 5-10 microM]. Chlorogenic acid, caffeic acid, or ferulic acid (100 microM) inhibited the metabolism of arachidonic acid to 5-HETE by 36, 10, or 16%, respectively, and these hydroxylated cinnamic acid derivatives inhibited the metabolism of arachidonic acid to 8-HETE by 37, 20, or 10%, respectively (IC50 greater than 100 microM). The metabolism of arachidonic acid to prostaglandin E2, prostaglandin F2 alpha, and prostaglandin D2 by epidermal microsomes was inhibited approximately 50% by the in vitro addition of 5-10 microM curcumin. Chlorogenic acid, caffeic acid, and ferulic acid (100 microM) were inactive. In vitro rat brain protein kinase C activity was not affected by 50-200 microM curcumin, chlorogenic acid, caffeic acid, or ferulic acid. The inhibitory effects of curcumin, chlorogenic acid, caffeic acid, and ferulic acid on TPA-induced tumor promotion in mouse epidermis parallel their inhibitory effects on TPA-induced epidermal inflammation and epidermal lipoxygenase and cyclooxygenase activities

TP53 mutation in colorectal cancer 334.

Iacopetta B.

Hum Mutat. 2003 Mar; 21(3):271-6.

Approximately half of all colorectal cancers show p53 (TP53) gene mutations, with higher frequencies observed in distal colon and rectal tumors and lower frequencies in proximal tumors and those with the microsatellite instability or methylator phenotypes. Alterations to this gene appear to have little or no prognostic value for colorectal cancer patients treated by surgery alone, but are associated with worse survival for patients treated with chemotherapy. There is some evidence that different p53 mutations are associated with different clinical features including prognosis and response to therapy, although further large studies are required to confirm this. Several in vitro, animal and clinical studies have shown that normal p53 is required for the response of colorectal cancers to 5-fluorouracil-based chemotherapy. This should be confirmed by additional retrospective cohort studies and by the incorporation of P53 status in ongoing and future clinical trials. The evaluation of p53 overexpression, using a standardized immunohistochemical (IHC) procedure, could be a clinically useful marker for the identification of colorectal cancer patients likely to benefit from the standard chemotherapy regime currently used for this disease

[Postoperative management of the preserved rectal segment in patients with familial polyposis: the use of 5-fluorouracil suppositories and green tea extract to inhibit tumor growth].

Ichikawa D, Takahashi T, Adachi T, et al.

Nippon Geka Gakkai Zasshi. 1998 Jun; 99(6):391-5.

We report the clinical details of seven patients with familial polyposis. They underwent subtotal colectomy with ileorectostomy, and were treated with 5-fluorouracil suppositories and green tea extract after surgery. Some regression of the polyps in the preserved rectal segment was observed, and no rectal cancer developed in any of these patients

Chemical form of selenium, critical metabolites, and cancer prevention.

Ip C, Hayes C, Budnick RM, et al.

Cancer Res. 1991 Jan 15; 51(2):595-600.

Methylated selenides are prominent metabolites at the dietary levels used for obtaining anticarcinogenic effects with selenium. The present study reports the chemopreventive activities of 2 novel selenium compounds, Se-methylselenocysteine and dimethyl selenoxide, in the rat dimethylbenz(a)anthracene-induced mammary tumor model. Other treatment groups were supplemented with either selenite or selenocystine for comparative purposes. Each selenium compound was tested at different levels and was given to the animal starting 1 week before dimethylbenz(a)anthracene administration and continued until sacrifice. Results of the carcinogenesis experiments showed that the relative efficacy with the four compounds was Se-methylselenocysteine greater than selenite greater than selenocystine greater than dimethyl selenoxide. In correlating the chemical form and metabolism of these selenium compounds with their anticarcinogenic activity, it is concluded that: (a) selenium compounds that are able to generate a steady stream of methylated metabolites, particularly the monomethylated species, are likely to have good chemopreventive potential; (b) anticarcinogenic activity is lower for selenoamino acids, such as selenocysteine following conversion from selenocystine, which have an escape mechanism via random, nonstoichiometric incorporation into proteins; and (c) forms of selenium, as exemplified by dimethyl selenoxide, which are metabolized rapidly and quantitatively to dimethyl selenide and trimethylselenonium and excreted, are likely to be poor choices. We also undertook a separate bioavailability study using Se-methylselenocysteine, dimethyl selenoxide, and trimethylselenonium as the starting compounds for delivering selenium with one, two, or three methyl groups, and measured the ability of these compounds to restore glutathione peroxidase activity in selenium-depleted animals. All three compounds were able to fully replete this enzyme, although with a wide range of efficiency (Se-methylselenocysteine greater than dimethyl selenoxide greater than trimethylselenonium), suggesting that complete demethylation to inorganic selenium is a normal process of selenium metabolism. However, the degree to which this occurs under chemoprevention conditions would argue against the involvement of selenoproteins in the anticarcinogenic action of these selenium compounds

Effects of fatty acids on liver metastasis of ACL-15 rat colon cancer cells.

Iwamoto S, Senzaki H, Kiyozuka Y, et al.

Nutr Cancer. 1998; 31(2):143-50.

The effects of eicosapentaenoic acid [EPA; n-3 polyunsaturated fatty acid (PUFA)], linoleic acid (LA; n-6 PUFA), and palmitic acid (PA; saturated fatty acid) on 1,2-dimethylhydrazine-induced F344 rat colon carcinoma cells (ACL-15) were investigated in vivo and in vitro. The number and size of liver metastatic foci via a superior mesenteric vein injection of ACL-15 cells in F344 rats were significantly inhibited in the EPA-treated group compared with the LA-treated group (p < 0.01); the PA-treated animals and those fed commercial rodent chow (standard diet) demonstrated intermediate values. In a dot immunoblotting assay, vascular cell adhesion molecule 1 expression on ACL-15 cells was downregulated by EPA-ethyl ester treatment and upregulated by LA-ethyl ester treatment compared with the untreated control cells, whereas the expression of matrix metalloproteinase 1 and 2 was not influenced by the fatty acid ethyl esters. In a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, EPA-ethyl ester suppressed ACL-15 cell growth in a schedule-dependent manner, and LA-ethyl ester showed schedule-dependent stimulation. In contrast, PA demonstrated no regulatory effect on cell growth at lower concentrations (< or = 5 mg/ml) but concentration-dependent inhibition at higher concentrations. According to our in vivo cell kinetic study, the difference in tumor growth at the metastatic site was due to different tumor cell proliferation rates; the cell loss rate was not altered. Therefore, the inhibitory effect of liver metastasis on ACL-15 cells by EPA can be explained by a decreased ability of tumor cell adhesion to the capillary bed (low expression of vascular cell adhesion molecule 1) and a lower potential of tumor cell proliferation (low mitotic rate) at the secondary site

Multivitamin use and colorectal cancer incidence in a US cohort: does timing matter?

Jacobs EJ, Connell CJ, Chao A, et al.

Am J Epidemiol. 2003 Oct 1; 158(7):621-8.

Multivitamins contain several nutrients, including folic acid, that are hypothesized to reduce the risk of colorectal cancer. Previous studies suggest that multivitamin use may reduce colorectal cancer risk but only after a long latency period. The authors examined the association between regular multivitamin use (four or more times per week) and colorectal cancer incidence among 145,260 men and women in the Cancer Prevention Study II Nutrition Cohort. Current multivitamin use was reported on a questionnaire at enrollment in 1992-1993. All participants had also reported multivitamin use on a questionnaire completed for a different study approximately 10 years earlier (in 1982). The authors observed 797 incident cases of colorectal cancer during follow-up from 1992 to 1997. After multivariate adjustment, regular multivitamin use at enrollment was not associated with risk of colorectal cancer (rate ratio = 1.04, 95% confidence interval: 0.87, 1.23), whereas regular multivitamin use 10 years before enrollment was associated with reduced risk (rate ratio = 0.71, 95% confidence interval: 0.57, 0.89). Regular multivitamin users 10 years before enrollment were at similarly reduced risk whether they were still regular multivitamin users at enrollment or had stopped. These results are consistent with the hypothesis that past, but not recent, multivitamin use may be associated with modestly reduced risk of colorectal cancer

Beta-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells.

Jaiswal AS, Marlow BP, Gupta N, et al.

Oncogene. 2002 Dec 5; 21(55):8414-27.

The development of nontoxic natural agents with chemopreventive activity against colon cancer is the focus of investigation in many laboratories. Curcumin (feruylmethane), a natural plant product, possesses such chemopreventive activity, but the mechanisms by which it prevents cancer growth are not well understood. In the present study, we examined the mechanisms by which curcumin treatment affects the growth of colon cancer cells in vitro. Results showed that curcumin treatment causes p53- and p21-independent G(2)/M phase arrest and apoptosis in HCT-116(p53(+/+)), HCT-116(p53(-/-)) and HCT-116(p21(-/-)) cell lines. We further investigated the association of the beta-catenin-mediated c-Myc expression and the cell-cell adhesion pathways in curcumin-induced G(2)/M arrest and apoptosis in HCT-116 cells. Results described a caspase-3-mediated cleavage of beta-catenin, decreased transactivation of beta-catenin/Tcf-Lef, decreased promoter DNA binding activity of the beta-catenin/Tcf-Lef complex, and decreased levels of c-Myc protein. These activities were linked with decreased Cdc2/cyclin B1 kinase activity, a function of the G(2)/M phase arrest. The decreased transactivation of beta-catenin in curcumin-treated HCT-116 cells was unpreventable by caspase-3 inhibitor Z-DEVD-fmk, even though the curcumin-induced cleavage of beta-catenin was blocked in Z-DEVD-fmk pretreated cells. The curcumin treatment also induced caspase-3-mediated degradation of cell-cell adhesion proteins beta-catenin, E-cadherin and APC, which were linked with apoptosis, and this degradation was prevented with the caspase-3 inhibitor. Our results suggest that curcumin treatment impairs both Wnt signaling and cell-cell adhesion pathways, resulting in G(2)/M phase arrest and apoptosis in HCT-116 cells

Nutrient intake patterns in gastric and colorectal cancers.

Jedrychowski W, Popiela T, Steindorf K, et al.

Int J Occup Med Environ Health. 2001; 14(4):391-5.

The purpose of the study was to present the dietary risk pattern in gastric and colorectal cancers, using the same methodological approach in a parallel hospital-based case-control study. In all, 180 cases of colorectal cancer and 80 cases of stomach cancer, confirmed histopathologically, were enrolled from the University Hospital in Cracow. A high intake of carbohydrates was associated with an increased risk of colorectal cancer (OR = 2.45). For stomach cancer, a moderate consumption of carbohydrates markedly increased relative risk (OR = 4.29), while a high intake of carbohydrates increased the risk by 8.73. The patterns of dietary risk factors related to intake of fats were definitively different in both cancer sites. The higher fat consumption was not associated with the higher risk of stomach cancer. A medium intake of fats increased the risk of colorectal cancer by 1.96 and that above 83 g/day by 2.20. In colorectal cancer, the significant protective effect of retinol, carotene and vitamin C has been evidenced, however, only carotene and vitamin E were inversely correlated with stomach cancer

Curcumin induces a p53-dependent apoptosis in human basal cell carcinoma cells.

Jee SH, Shen SC, Tseng CR, et al.

J Invest Dermatol. 1998 Oct; 111(4):656-61.

Curcumin, a potent antioxidant and chemopreventive agent, has recently been found to be capable of inducing apoptosis in human hepatoma and leukemia cells by way of an elusive mechanism. Here, we demonstrate that curcumin also induces apoptosis in human basal cell carcinoma cells in a dose- and time-dependent manner, as evidenced by internucleosomal DNA fragmentation and morphologic change. In our study, consistent with the occurrence of DNA fragmentation, nuclear p53 protein initially increased at 12 h and peaked at 48 h after curcumin treatment. Prior treatment of cells with cycloheximide or actinomycin D abolished the p53 increase and apoptosis induced by curcumin, suggesting that either de novo p53 protein synthesis or some proteins synthesis for stabilization of p53 is required for apoptosis. In electrophoretic mobility gel-shift assays, nuclear extracts of cells treated with curcumin displayed distinct patterns of binding between p53 and its consensus binding site. Supportive of these findings, p53 downstream targets, including p21(CIP1/WAF1) and Gadd45, could be induced to localize on the nucleus by curcumin with similar p53 kinetics. Moreover, we immunoprecipitated extracts from basal cell carcinoma cells with different anti-p53 antibodies, which are known to be specific for wild-type or mutant p53 protein. The results reveal that basal cell carcinoma cells contain exclusively wild-type p53; however, curcumin treatment did not interfere with cell cycling. Similarly, the apoptosis suppressor Bcl-2 and promoter Bax were not changed with the curcumin treatment. Finally, treatment of cells with p53 antisense oligonucleotide could effectively prevent curcumin-induced intracellular p53 protein increase and apoptosis, but sense p53 oligonucleotide could not. Thus, our data suggest that the p53-associated signaling pathway is critically involved in curcumin-mediated apoptotic cell death. This evidence also suggests that curcumin may be a potent agent for skin cancer prevention or therapy

Green tea consumption and the risk of pancreatic and colorectal cancers.

Ji BT, Chow WH, Hsing AW, et al.

Int J Cancer. 1997 Jan 27; 70(3):255-8.

The effect of green tea drinking in reducing human cancer risk is unclear, though a protective effect has been reported in numerous animal studies and several epidemiologic investigations. Herein the hypothesis that green tea consumption may reduce the risk of cancers of the colon, rectum and pancreas is examined in a large population-based case-control study conducted in Shanghai, China. Newly diagnosed cancer cases (931 colon, 884 rectum and 451 pancreas) during 1990-1993 among residents 30-74 years of age were included. Controls (n = 1,552) were selected among Shanghai residents and frequency-matched to cases by gender and age. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) of each cancer associated with green tea consumption were derived after adjustment for age, income, education and cigarette smoking. Additional adjustment for dietary items and body size was found to have minimal impact. An inverse association with each cancer was observed with increasing amount of green tea consumption, with the strongest trends for rectal and pancreatic cancers. For men, compared with non-regular tea drinkers, ORs among those in the highest tea consumption category (> or = 300 g/month) were 0.82 for colon cancer, 0.72 for rectal cancer and 0.63 for pancreatic cancer, with p values for trend being 0.38, 0.04 and 0.04, respectively. For women, the respective ORs for the highest consumption category (> or = 200 g/month) were 0.67, 0.57 and 0.53, with the respective p values for trend being 0.07, 0.001 and 0.008. Our findings provide further evidence that green tea drinking may lower the risk of colorectal and pancreatic cancers

[Effects of tea on aberrant crypt foci and colorectal tumors in rats].

Jia X, Wang W, Cui W, et al.

Wei Sheng Yan Jiu. 2000 Jan 30; 29(1):54-6.

The present study was designed to investigate the chemopreventive effects of green tea and tea pigments (the main component of black tea) on 1,2-dimethylhydrazine (DMH)-induced rat colorectal carcinogenesis. Compared with the positive control group, green tea and tea pigments groups had less numbers of aberrant crypt foci (ACF) (P < 0.01) at the end of week 16. At the end of week 32, all rats in the positive control group developed colorectal tumors with an average of 2.6 tumors per rat, and a mean volume of 294.7 mm3 per tumor, while in the groups drinking green tea and tea pigments, the average numbers of colorectal tumors per rat were only 47.1% and 43.1% of controls respectively, and the mean tumor volume was inhibited by 77.1% and 68.1% respectively. It was concluded that tea pigments had a chemopreventive effect on colorectal tumor and ACF formation can be used as a useful intermediate end point to study chemopreventive effects on colorectal cancer

Chemoprevention of tea on colorectal cancer induced by dimethylhydrazine in Wistar rats.

Jia XD, Han C.

World J Gastroenterol. 2000 Oct; 6(5):699-703.

AIM:To investigate the chemopreventive effects of green tea and tea pigment on 1,2-dimethylhydrazine (DMH)-induced rat colorectal carcinogenesis.METHODS:Male weaning Wistar rats were randomly allocated into four groups.Rats in the positive control group were given a(c)s.c. injection of DMH, once a week for ten weeks;rats in tea treated groups, with the same DMH treatment as in the positive group, received 2% green tea and 0.1% tea pigments; rats in the negative control group were given s.c.injection of the same volume of saline as well as DMH in the positive group. Animals were sacrified and necropsied at the end of week 16 and week 32.RESULTS:Aberrant cryptic foci (ACF) were formed in animals in DMH-treated groups at the end of week 16. Compared to the DMH group, green tea and tea pigments groups had less ACF (148.25 and 204.25, respectively, P<0.01). At the end of week 32, all rats in DMH group developed large intestinal tumors. The results also showed that DMH increased labeling index (LI) of proliferating cell nuclear antigen (PCNA) of intestinal mucosa and the expression of ras-p21. However, in the tea-treated groups, PCNA-LI was significantly reduced as compared with the positive control group (36.63 and 40.36 in the green tea group and tea pigment group, respectively, at the end of the experiment,P<0.01).ras-p21 expression was also significantly reduced (2.07 and 2.36 in the colon tumors of rats in the green tea group and tea pigments group, respectively at the end of the experiment, P<0.01). Furthermore, green tea and tea pigment inhibited the expression of Bcl-2 protein (2, 5, 1, 0 and 2, 4, 1, 0,respectively, at the end of the experiment P<0.01), and induced expression of Bax protein (0,1,3,4 and 0,1,4,3, respectively, P <0.01).CONCLUSION:Chinese green tea drinking inhibited ACF and colonic tumors formation in rats, which showed that tea had a significant chemopreventive effect on DMH-induced colorectal carcinogenesis. Such effects may be due to suppression of cell proliferation and induction of apoptosis in the intestinal crypts

Dietary influence on some proposed risk factors for colon cancer: fecal and urinary mutagenic activity and the activity of some intestinal bacterial enzymes.

Johansson G, Holmen A, Persson L, et al.

Cancer Detect Prev. 1997; 21(3):258-66.

This investigation studied the effects of a shift from a well-balanced mixed diet to a lacto-vegetarian diet on the mutagenic activity in urine and feces and on some cancer-associated bacterial enzymes in human feces (beta-glucuronidase, beta-glucosidase, and sulphatase). Three months after the shift to the lacto-vegetarian diet, there was a significant decrease in mutagenic activity in urine and feces, beta-glucuronidase, beta-glucosidase, and sulphatase per gram feces wet weight. In contrast, the fecal mutagenic activity and the enzyme activities remained unchanged if expressed per daily output. However, the urinary mutagenic activity expressed as total daily output decreased. Part of the explanation for the decreased fecal mutagenic activity and the decreased enzyme activities is obviously a dilution effect, because much of the increased fecal weight after the shift in diet was associated with a higher water content

Arachidonic acid and colorectal carcinogenesis 471.

Jones R, Adel-Alvarez LA, Alvarez OR, et al.

Mol Cell Biochem. 2003; 253(1-2):141-9.

Colorectal carcinoma is a leading cause of cancer related death worldwide. This deadly disease advances through a series of clinical and histopathological stages, initiated by single crypt lesions to small benign tumors and finally to malignancy. Although some progress has been made in elucidating the formation of colorectal tumors at molecular/genetic levels, the possible mechanisms of dietary lipids in inducing and promoting colorectal tumorigenesis are poorly understood. Recent epidemiological studies, however, indicate that lipid-rich diet containing omega-6 fatty acids (i.e. linoleic acid, arachidonic acid, etc.) may somehow be related with the disease process. Rapid metabolism of arachidonic acid, increased activities of phospholipases (i.e. phospholipase-A2s), and the elevated levels of cyclooxygenase (COX) and lipoxygenase (LOX) in colonic cells were reported in various stages of the malignancy, suggesting a possible link between dietary lipids and the incidence of colorectal cancer. The major focus of this review is to delineate the recent findings on enhanced arachidonic acid metabolism and its conversion into eicosanoids during the initiation and progression of colorectal carcinogenesis. In addition, the identification and participation of various phospholipases are also discussed. It is speculated that many of these phospholipases can be used as targets for developing new drugs against colorectal as well as other adenocarcinomas

Arachidonic acid and colorectal carcinogenesis.

Jones R, Adel-Alvarez LA, Alvarez OR, et al.

Mol Cell Biochem. 2003 Nov; 253(1-2):141-9.

Colorectal carcinoma is a leading cause of cancer related death worldwide. This deadly disease advances through a series of clinical and histopathological stages, initiated by single crypt lesions to small benign tumors and finally to malignancy. Although some progress has been made in elucidating the formation of colorectal tumors at molecular/genetic levels, the possible mechanisms of dietary lipids in inducing and promoting colorectal tumorigenesis are poorly understood. Recent epidemiological studies, however, indicate that lipid-rich diet containing omega-6 fatty acids (i.e. linoleic acid, arachidonic acid, etc.) may somehow be related with the disease process. Rapid metabolism of arachidonic acid, increased activities of phospholipases (i.e. phospholipase-A2s), and the elevated levels of cyclooxygenase (COX) and lipoxygenase (LOX) in colonic cells were reported in various stages of the malignancy, suggesting a possible link between dietary lipids and the incidence of colorectal cancer. The major focus of this review is to delineate the recent findings on enhanced arachidonic acid metabolism and its conversion into eicosanoids during the initiation and progression of colorectal carcinogenesis. In addition, the identification and participation of various phospholipases are also discussed. It is speculated that many of these phospholipases can be used as targets for developing new drugs against colorectal as well as other adenocarcinomas

EGCG, a major component of green tea, inhibits tumour growth by inhibiting VEGF induction in human colon carcinoma cells.

Jung YD, Kim MS, Shin BA, et al.

Br J Cancer. 2001 Mar 23; 84(6):844-50.

Catechins are key components of teas that have antiproliferative properties. We investigated the effects of green tea catechins on intracellular signalling and VEGF induction in vitro in serum-deprived HT29 human colon cancer cells and in vivo on the growth of HT29 cells in nude mice. In the in vitro studies, (-)-epigallocatechin gallate (EGCG), the most abundant catechin in green tea extract, inhibited Erk-1 and Erk-2 activation in a dose-dependent manner. However, other tea catechins such as (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epicatechin (EC) did not affect Erk-1 or 2 activation at a concentration of 30 microM. EGCG also inhibited the increase of VEGF expression and promoter activity induced by serum starvation. In the in vivo studies, athymic BALB/c nude mice were inoculated subcutaneously with HT29 cells and treated with daily intraperitoneal injections of EC (negative control) or EGCG at 1.5 mg day(-1)mouse(-1)starting 2 days after tumour cell inoculation. Treatment with EGCG inhibited tumour growth (58%), microvessel density (30%), and tumour cell proliferation (27%) and increased tumour cell apoptosis (1.9-fold) and endothelial cell apoptosis (3-fold) relative to the control condition (P< 0.05 for all comparisons). EGCG may exert at least part of its anticancer effect by inhibiting angiogenesis through blocking the induction of VEGF

Inhibition of tumour invasion and angiogenesis by epigallocatechin gallate (EGCG), a major component of green tea.

Jung YD, Ellis LM.

Int J Exp Pathol. 2001 Dec; 82(6):309-16.

Epidemiological studies have suggested that consumption of green tea may decrease cancer risk. In addition, abundant pre-clinical data from several laboratories have provided convincing evidence that polyphenols present in green tea afford protection against cancer in both in vivo and in vitro studies. Recently, epigallocatechin gallate (EGCG), a putative chemopreventive agent and a major component of green tea, was reported to inhibit tumour invasion and angiogenesis, processes that are essential for tumour growth and metastasis. Understanding the basic principles by which EGCG inhibits tumour invasion and angiogenesis may lead to the development of new therapeutic strategies, in addition to supporting the role of green tea as a cancer chemopreventive agent

Retinoids inhibit protein kinase C-dependent transduction of 1,2-diglyceride signals in human colonic tumor cells.

Kahl-Rainer P, Marian B.

Nutr Cancer. 1994; 21(2):157-68.

1,2-Diglycerides with long-chain fatty acid residues related to nutritional fat (LCDGs) specifically affect growth and urokinase secretion in human colonic tumor cells, but not in normal mucosa. This allows them to advance and enhance carcinogenesis in the colon and rectum. SW480 colon carcinoma cells are LCDG sensitive in the same way as primary colonic tumor cells and have therefore been used as a model system to study the mechanism of LCDG action and to search for inhibitors of tumor development in the colon. Using this model system, we have shown that the effects of LCDGs are transmitted by protein kinase C and abolished by downregulation of the enzyme. Retinol, retinoic acid, and beta-carotene in nanomolar concentrations inhibit LCDG-induced growth and urokinase secretion and block stimulation of protein kinase C. Although retinol and retinoic acid at higher concentrations also display stimulatory activity, beta-carotene does not. At 100 nM, a concentration that can easily be reached in the plasma of humans, beta-carotene reduces LCDG-induced urokinase secretion about 50%. Inasmuch as beta-carotene does not have side effects due to intrinsic activities and storage effects, beta-carotene and foods rich in carotenes could be useful in the prevention of colorectal cancer

HISTAMINE.

KAHLSON G, ROSENGREN E.

Annu Rev Pharmacol. 1965; 10:305-20.

Endoscopic ultrasonography in the preoperative staging of colorectal cancer.

Kalantzis C, Markoglou C, Gabriel P, et al.

Hepatogastroenterology. 2002 May; 49(45):683-6.

BACKGROUND/AIMS: Endoscopic ultrasonography presents a significant progress in imaging methods for the examination of the digestive system and is commonly used in cancer staging. The aim of this study was to quantify the potential of this modality for diagnosis and staging of colorectal cancer. METHODOLOGY: Eighty patients with histologically proven colorectal cancer were included in this study. All patients were preoperatively diagnosed by colonoscopy and biopsies, abdominal computed tomography and endoscopic ultrasonography. The latter was also used to evaluate the depth of tumor invasion and presence of lymph node or distant metastasis prior to surgery. RESULTS: Endoscopic ultrasonography presented 100% sensitivity in cancer detection versus 60% for computed tomography (P < 0.001). Endoscopic Ultrasonography sensitivity in T, N, M and TNM staging was 93.8%, 93.8%, 92.5% and 82.5% with corresponding specificities of 99.2%, 97.9%, 92.5% and 94.2%. Overall, Endoscopic Ultrasonography staging of the patients did not present statistically significant differences with histological staging (P > 0.05). CONCLUSIONS: Endoscopic ultrasonography is of satisfactory accuracy in diagnosis and preoperative staging of colorectal cancer

Ratio of primary and secondary bile acids in feces: possible marker for colorectal cancer? 3.

Kamano T, Mikami Y, Kurasawa T, et al.

Dis Colon Rectum. 1999 May; 42(5):668-72.

PURPOSE: Increases in fecal bile acids may play a role in colorectal carcinogenesis. The authors tested the hypothesis that high concentrations of primary and secondary bile acids are more common in patients with colon cancer than in patients with other gastrointestinal diseases. METHODS: In this retrospective study the secondary bile acid deoxycholic acid and the primary bile acid cholic acid were measured in the feces by enzyme-linked immunoabsorbent assay in 63 patients with colorectal cancer, 24 patients with gastric cancer, 11 patients with biliary disorders, and 47 healthy volunteers. RESULTS: Preoperatively, the mean deoxycholic acid values tended to be higher and the cholic acid values were significantly lower in patients with colorectal cancer than in healthy subjects. Patients with other gastrointestinal diseases had lower deoxycholic acid and cholic acid values than healthy subjects. In healthy subjects the deoxycholic acid to cholic acid ratio ranged from 0.10 to 2.86 (mean, 0.88), but in almost two-thirds, the ratio did not exceed 1. In contrast, the mean preoperative ratio in patients with colorectal cancer was 2.26 (range, 0.06-7.17; P < 0.0001) and tended to be higher in patients with advanced cancer and in those with sigmoid and rectal tumors. If 1.1 is taken as the upper limit of normal for deoxycholic acid to cholic acid ratio, 67 percent of patients with colorectal cancer had an abnormal value preoperatively. CONCLUSION: A high deoxycholic acid concentration and deoxycholic acid to cholic acid ratio may be indicators of colorectal cancer. Further study is needed to improve sensitivity and specificity, perhaps by combining fecal bile acid measurements with other tests, and a large prospective trial may be warranted to determine whether these measurements have value in screening for this common cancer

Routine (18)F-FDG PET preoperative staging of colorectal cancer: comparison with conventional staging and its impact on treatment decision making.

Kantorova I, Lipska L, Belohlavek O, et al.

J Nucl Med. 2003 Nov; 44(11):1784-8.

The preoperative staging of colorectal cancer (CRC) with (18)F-FDG PET is not as yet generally considered to be evidence based. We have found only 1 study that evaluated (18)F-FDG PET in a nonselected population with proven CRC. Several other studies have concentrated on more advanced disease. The aim of this study was to assess the potential clinical benefit of (18)F-FDG PET in the routine staging of CRC. METHODS: Thirty-eight consecutive patients who had had CRC histologically proven by colonoscopy underwent prospective preoperative staging by plain chest radiography, sonography, CT, and (18)F-FDG PET. Sensitivity, specificity, and accuracy were retrospectively assessed by comparison with the histologic results after surgery (36 patients) or clinical follow-up (2 inoperable cases-both patients died within 1 y of the PET examination). The impact of (18)F-FDG PET on therapeutic decision making was evaluated by comparing medical records before and after (18)F-FDG PET. RESULTS: (18)F-FDG PET correctly detected 95% of primary tumors, whereas CT and sonography correctly detected only 49% and 14%, respectively. Lymph nodes were involved in 7 patients. The sensitivity, specificity, and accuracy of (18)F-FDG PET were 29%, 88%, and 75%, respectively. CT and sonography did not reveal any lymph node involvement. Liver metastases were present in 9 patients. (18)F-FDG PET, CT, and sonography had a sensitivity of 78%, 67%, and 25%, respectively; a specificity of 96%, 100%, and 100%, respectively; and an accuracy of 91%, 91%, and 81%, respectively. (18)F-FDG PET revealed further lesions in 11 patients. Levels of carcinoembryonic antigen and carbohydrate antigen 19-9 tumor markers were elevated in, respectively, only 33% and 8% of cases of proven CRC. (18)F-FDG PET changed the treatment modality for 8% and the range of surgery for 13% of patients. In total, (18)F-FDG PET changed the method of treatment for 16% of patients. CONCLUSION: Plain chest radiography and sonography did not bring any clinical benefits. No correlation was found between the level of tumor markers and the stage of disease. CT is necessary for confirmation of PET findings at extraabdominal sites (PET-guided CT) and for their morphologic specification at abdominal and pelvic sites before an operation. (18)F-FDG PET is the best method for the staging of CRC in all localities, despite the high rate of false-negative PET findings in patients with lymph node involvement. PET should be performed as a first examination after verification of CRC. We propose a PET/CT hybrid system as optimal in the staging of CRC

Increased risk of cancer in ulcerative colitis: a population-based cohort study.

Karlen P, Lofberg R, Brostrom O, et al.

Am J Gastroenterol. 1999 Apr; 94(4):1047-52.

OBJECTIVE: There is an increased risk of colorectal cancer among patients with ulcerative colitis (UC). However, the overall and site specific cancer risks in these patients have been investigated to a limited extent. To study the association between UC and cancer, a population-based study of 1547 patients with UC in Stockholm diagnosed between 1955 and 1984 was carried out. METHODS: The patients were followed in both the National Cancer Register and the National Cause of Death Register until 1989. For comparisons, regional cancer incidence rates in Stockholm County were used together with individually computed person-years at risk in the UC disease cohort. RESULTS: A total of 121 malignancies occurred among 97 individuals as compared with 89.8 expected (standardized morbidity ratio [SMR] = 1.4; 95% confidence interval (CI), 1.1-1.6). Overall, an excess number of colorectal cancers (SMR, 4.1; 95% CI, 2.7-5.8), and hepatobiliary cancers in men (SMR = 6.0; 95% CI, 2.8-11.1) associated with primary sclerosing cholangitis, was observed. The risk of pulmonary cancer was decreased (SMR = 0.3; 95% CI, 0.1-0.9). In all, 91 extracolonic malignancies were observed, compared with the 82.3 expected (SMR = 1.11; 95% CI, 0.9-1.3). CONCLUSIONS: In UC patients, the overall cancer incidence is increased mainly because of an increased incidence of colorectal and hepatobiliary cancer. This increase is partly counterbalanced by a decreased risk of pulmonary cancer compared with that in the general population

Serum folate, homocysteine and colorectal cancer risk in women: a nested case-control study.

Kato I, Dnistrian AM, Schwartz M, et al.

Br J Cancer. 1999 Apr; 79(11-12):1917-22.

Accumulating evidence suggests that folate, which is plentiful in vegetables and fruits, may be protective against colorectal cancer. The authors have studied the relationship of baseline levels of serum folate and homocysteine to the subsequent risk of colorectal cancer in a nested case-control study including 105 cases and 523 matched controls from the New York University Women's Health Study cohort. In univariate analyses, the cases had lower serum folate and higher serum homocysteine levels than controls. The difference was more significant for folate (P < 0.001) than for homocysteine (P = 0.04). After adjusting for potential confounders, the risk of colorectal cancer in the subjects in the highest quartile of serum folate was half that of those in the lowest quartile (odds ratio, OR = 0.52, 95% confidence interval, CI = 0.27-0.97, P-value for trend = 0.04). The OR for the highest quartile of homocysteine, relative to the lowest quartile, was 1.72 (95% CI = 0.83-3.65, P-value for trend = 0.09). In addition, the risk of colorectal cancer was almost twice as high in subjects with below-median serum folate and above-median total alcohol intake compared with those with above-median serum folate and below-median alcohol consumption (OR = 1.99, 95% CI = 0.92-4.29). The potentially protective effects of folate need to be confirmed in clinical trials

Randomized trial of preoperative cimetidine in patients with colorectal carcinoma with quantitative assessment of tumor-associated lymphocytes.

Kelly MD, King J, Cherian M, et al.

Cancer. 1999 Apr 15; 85(8):1658-63.

BACKGROUND: Previous studies have suggested that cimetidine, a histamine-2 receptor antagonist with immunostimulatory effects, may improve survival in patients with colorectal carcinoma. This effect may be apparent by an increase in the number of peritumoral lymphocytes. A prospective, double blind, randomized, placebo-controlled trial of a short course of preoperative treatment with cimetidine in patients with colorectal carcinoma was performed to assess the effect of cimetidine on survival and on the number of peritumoral lymphocytes. METHODS: One hundred and twenty-five patients who were scheduled to undergo elective colon or rectal excision for carcinoma were randomized to receive either placebo or cimetidine preoperatively for 5 days. In addition to standard histopathology, immunohistochemistry and computer video image analysis were used to assess the number of peritumoral lymphocytes in an objective manner. Interim survival analysis according to the Kaplan-Meier method was performed. RESULTS: A trend toward a survival advantage in the group of patients receiving cimetidine (800 mg twice daily) compared with the placebo group was observed (P = 0.20, log rank test) that was most marked in patients with replication error negative tumors (P = 0.04). Similarly, in these two groups there was a trend toward an increase in the number of patients with a conspicuous lymphocytic infiltration (P = 0.10, chi-square test). However, there was no difference in the number of peritumoral lymphocytes as measured by image analysis. CONCLUSIONS: Based on the results of the current study, a short course of preoperative treatment with cimetidine does appear to have an effect on patient survival; however, the exact mechanism is unknown. The failure of this study to demonstrate a clear increase in the local lymphocyte response does not exclude an immunologic mechanism of action

The changed histologic paradigm of colorectal polyps.

Khan A, Shrier I, Gordon PH.

Surg Endosc. 2002; 16(3):436-40.

BACKGROUND: Previous literature has recorded the preponderance of hyperplastic over neoplastic polyps. This study evaluated the histopathologic characteristics of colonic polyps, excised during colonoscopic polypectomy, and further determined their relationship to age, location, and gender. METHODS: Of 5132 colonoscopies reviewed between 1976 and 1999, 757 were performed on 582 patients who had polyp removal. Patients with previous colon resection or incomplete cecal intubation were excluded. RESULTS: The mean age was 67 +/- 11 years for men and 66 +/- 11 years for women. Of the 1050 lesions histologically analyzed, 871 (83.0%) were neoplastic, 129 (12.3%) were hyperplastic, and 50 (4.8%) were miscellaneous lesions (29 inflammatory polyps, 14 lipomas, 2 leiomyomas, 1 juvenile polyp, and 4 no pathology identified). Hyperplastic polyps were always less than 1 cm (with one exception) and were located predominantly in the left colon, the majority residing in the sigmoid colon. Peak prevalence of hyperplastic polyps occurred in the 50-70 years old age group. Of the neoplastic polyps, 566 (65.0%) were tubular, 225 (25.8%) villotubular, 63 (7.2%) villous adenomas, 4 (0.5%) mixed adenomatous hyperplastic polyps, and 12 (1.4%) invasive carcinomas. The peak prevalence of neoplastic polyps occurred in the same age group as did hyperplastic polyps. Even though adenomatous polyps outnumbered hyperplastic polyps throughout the colon and within each age group, a greater percentage of hyperplastic polyps were found distally and in younger patients compared to location and age groups for neoplastic polyps. CONCLUSION: Adenomatous polyps outnumber hyperplastic polyps 7:1, even in the distal colon. Even small polyps seen during colonoscopy should be removed and subjected to histologic analysis because of the advisability of follow-up examinations of patients with neoplastic polyps. The increase in the incidence of neoplastic polyps beginning at the age of 50 years supports the need for colonoscopy in these individuals

Effect of folate supplementation on mucosal cell proliferation in high risk patients for colon cancer.

Khosraviani K, Weir HP, Hamilton P, et al.

Gut. 2002 Aug; 51(2):195-9.

AIMS: Intracellular folate deficiency has been implicated in colonic carcinogenesis in epidemiological studies and animal and human cancer models. Our aim was to determine the effect of folate supplementation on patients with recurrent adenomatous polyps using rectal mucosal cell proliferation as a biomarker. PATIENTS AND METHODS: Eleven patients with recurrent adenomatous polyps of the colon were randomised into a treatment group (n=6) receiving a dietary supplement of 2 mg folic acid per day for three months and a control group (n=5) receiving a placebo. Rectal biopsies where taken at 10 cm from the anal verge prior to supplementation and repeated at four, 12, and 18 weeks from the start of the supplementation. Each biopsy was immediately incubated in culture medium enriched with bromodeoxyuridine (BrdU). The S phase cells which incorporated BrdU into their DNA were identified following immunohistochemical staining. Twenty five orientated crypts were identified for each time point and the number and position of BrdU positive and BrdU negative cells were counted. BrdU labelling indices (LIs) were calculated for the entire crypt and for each of five equal compartments running consequently from the base to the luminal surface. RESULTS: The LI of the treatment group (9.1 (6.7, 12.3)) and the control group (9.3 (7.8, 10.3)) were comparable at the start. Over the duration of the supplementation period, LI in the control group did not alter significantly (9.3 (7.8, 10.3) v 9.6 (8.9, 10.4)). However, LI of the folate treated group was lowered after 12 weeks of supplementation (9.1 (6.7, 12.3) v 7.4 (5.3, 9.6)). Analysis of the LI for compartments within the crypt showed that the most significant drop in number of proliferating cells was in the upper most regions of the crypt. CONCLUSION: These data indicate that (a) folate supplementation decreases colonic mucosal cell proliferation in a high risk group for colon cancer and (b) the most significant reduction takes place at the luminal aspect of the crypt

Role of folate in colon cancer development and progression.

Kim YI.

J Nutr. 2003 Nov; 133(11 Suppl 1):3731S-9S.

Folate, a water-soluble B vitamin and important cofactor in 1-carbon transfer, is an important nutritional factor that may modulate the development of colorectal cancer. Epidemiologic and clinical studies indicate that dietary folate intake and blood folate levels are inversely associated with colorectal cancer risk. Collectively, these studies suggest an approximately 40% reduction in the risk of colorectal cancer in individuals with the highest dietary folate intake compared with those with the lowest intake. Animal studies using chemical and genetically predisposed rodent models have provided considerable support for a causal relationship between folate depletion and colorectal carcinogenesis as well as a dose-dependent protective effect of folate supplementation. However, animal studies have also shown that the dose and timing of folate intervention are critical in providing safe and effective chemoprevention; exceptionally high supplemental folate levels and folate intervention after microscopic neoplastic foci are established in the colorectal mucosa promote rather than suppress colorectal carcinogenesis. These animal studies in conjunction with clinical observations suggest that folate possesses the dual modulatory effects on carcinogenesis depending on the timing and dose of folate intervention. Folate deficiency has an inhibitory effect whereas folate supplementation has a promoting effect on progression of established neoplasms. In contrast, folate deficiency in normal epithelial tissues appears to predispose them to neoplastic transformation, and modest levels of folate supplementation suppress the development of tumors in normal tissues. Notwithstanding the limitations associated with animal models, these animal studies suggest that the optimal timing and dose of folate intervention need to be established for safe and effective chemoprevention in humans

Vitamin E: Mechanisms of Action as Tumor Cell Growth Inhibitors.

Kline K, Yu W, Sanders BG.

J Nutr. 2001 Jan 1; 131(1):161S-163.

Cimetidine inhibits cancer cell adhesion to endothelial cells and prevents metastasis by blocking E-selectin expression 375.

Kobayashi K, Matsumoto S, Morishima T, et al.

Cancer Res. 2000 Jul 15; 60(14):3978-84.

Although the beneficial effect of cimetidine on survival in cancer has been clinically demonstrated in colorectal cancer patients, the mode of action of cimetidine has not been elucidated. In this report, we have demonstrated for the first time that cimetidine can block the adhesion of a colorectal tumor cell line to the endothelial cell monolayer in cell culture and that it can suppress the metastasis of the tumor cell in a nude mouse model. We also demonstrated that these antimetastasis effects of cimetidine might occur through down-regulation of the cell surface expression of E-selectin on endothelial cells, a ligand for sialyl Lewis antigens on tumor cells. We found that the cimetidine-mediated down-regulation of E-selectin did not involve down-regulation of E-selectin mRNA or blocking of the nuclear translocation of nuclear factor kappaB, a transcriptional activator of E-selectin gene expression. Because two other histamine type 2 receptor antagonists, famotidine and ranitidine, did not show any similar effect, these actions of cimetidine probably do not occur via blocking of the histamine receptor. These observations support the idea that cancer metastasis can be blocked by cimetidine administration through blocking the adhesion of tumor cells to the endothelium when an interaction between E-selectin and sialyl-Lewis antigens plays a role

omega-3 fatty acids decrease endothelial adhesion of human colorectal carcinoma cells.

Kontogiannea M, Gupta A, Ntanios F, et al.

J Surg Res. 2000 Aug; 92(2):201-5.

BACKGROUND: Diets rich in omega-3 fatty acids have been shown to decrease both the initiation and promotion of colon carcinogenesis although their effect on hepatic metastasis formation is less well understood. Since adhesion of human colorectal carcinoma (HCRC) cells to hepatic endothelial cells is an important step in the metastatic cascade, the effect of membrane omega-3 fatty acid alterations on endothelial cell adhesion was studied. MATERIALS AND METHODS: CX-1 cells, a moderately differentiated HCRC cell line known to produce hepatic metastases in an athymic mouse intrasplenic injection model, were used. Cells were grown in omega-3 fatty acid-enriched medium and membrane-free fatty acid modifications confirmed with gas chromatography. Both human umbilical vein and hepatic sinusoidal endothelial cells were used in the binding assays. Adhesion assays were performed in a standard fashion using (51)Cr-labeled cells to tumor necrosis factor (TNF)-stimulated endothelial cell monolayers. Immunohistochemical analysis was performed for sialyl-Lewis(x), the receptor involved in endothelial adhesion on the surface of control and fatty acid-modified cells. RESULTS: Gas chromatographic analysis confirmed membrane fatty acid modification of CX-1 cells by growth in docosahexanoic acid (omega-3) (4.761 nmol/10(6) cells vs 0.057 nmol/10(6) cells for controls). Binding of CX-1 to both human umbilical vein and hepatic sinusoidal endothelial cells decreased from 38.4 +/- 0.44 to 11.58 +/- 0.87% (P < 0.01). Immunocytochemical analysis showed a decrease in sialyl-Lewis(x) expression with omega-3 treatment. CONCLUSIONS: These data indicate that omega-3 fatty acids may also be protective against the formation of hepatic metastases. The mechanism for this may be decreased endothelial cell adhesion which in turn may be due to decreased expression of the endothelial receptor sialyl-Lewis(x)

Tumour's angiogenesis--the function of VEGF and bFGF in colorectal cancer.

Kos M, Dabrowski A.

Ann Univ Mariae Curie Sklodowska [Med ]. 2002; 57(2):556-61.

The main objective of this paper was to present the view on the vascular endothelial growth factor (VEGF) and basis fibroblast growth factor (bFGF) in the angiogenesis in the colorectal career. The analysis includes the works of these scientists, who proved the relationship between VEGF and bFGF expression and the advancement level of colorectal cancer and the survival of the patients ill with this disease. It was stated that the highest levels of these factors were connected with the advancement of neoplastic process, especially when metastases coexisted at the same time. It was also proved that the higher levels of VEGF and bFGF gave worse prognosis as far as survival was concerned. Apart from this, other factors effecting angiogenesis and inhibiting factors were also presented

[Role and significance of DNA methylation].

Kowal M, Wojcierowski J.

Pol Merkuriusz Lek. 2003 Apr; 14(82):364-8.

DNA methylation is covalent addition of a methyl group to cytosine within the CpG dinucleotide. It has profound effects on the mammalian genome. These effects include transcriptional repression via inhibition of transcription factor binding, X chromosome inactivation, and imprinting. DNA methylation is important for both DNA repair and genome stability. Normal methylation patterns are frequently disrupted in tumour cells with global hypomethylation accompanying region-specific hypermethylation. When this hypermethylation occurs within the promoter of a tumour suppressor gene it could silence the gene and provide the cell with a growth advantage in a way similar to deletions or mutations. There is considerable evidence suggesting that alterations in DNA methylation play an important role in tumorigenesis and tumour progression

Significance of the evaluation of the tissue proliferation specific marker (TPS) and the carcinoembryonal antigen (CEA) in patients with ulcerative colitis and adenocarcinoma.

Krauss H, Ignys I, Kopczynski Z, et al.

Med Sci Monit. 2002 Jan; 8(1):CR48-CR51.

BACKGROUND: The aim of our research was to evaluate TPS concentration as a marker of proliferative processes and the levels of CEA in children and adults with ulcerative colitis (UC) and in adults with colorectal adenocarcinoma (AC), to find out if there is any interdependence between TPS and CEA concentrations in these patients and to evaluate the usefulness of TPS as a marker of neoplastic risk in patients with UC. MATERIAL/METHODS: The study was carried out in 3 groups of patients: Group I consisted of 15 children, ages 10-18, treated for UC; Group II, 22 adults, ages 23-40, treated for UC; and Group III, 14 patients, ages 40-60, in whom AC was diagnosed. RESULTS: In Group II, the mean TPS concentration was significantly higher than in Group I (p<0.00001). In Group III, adults with AC, the mean TPS concentration was 1074.00+/-1356.87 U/l. Thus there was a statistically significant difference between TPS concentrations in adults with UC and adults with AC (p<0.00005). There was no statistically significant difference between CEA levels in children and adult groups with UC. However, a statistically significant difference occurred between CEA concentrations in children and adults with UC and the group of adults with AC (p<0.00001). CONCLUSIONS: It would appear that testing for TPS concentration in patients with UC is helpful in monitoring the proliferative process, whereas in patients with neoplastic processes it serves as a screening examination, enabling early detection of recurrences, full evaluation of neoplastic growth, and evaluation of therapeutic effectiveness

Cimetidine modulates the antigen presenting capacity of dendritic cells from colorectal cancer patients 372.

Kubota T, Fujiwara H, Ueda Y, et al.

Br J Cancer. 2002 Apr 22; 86(8):1257-61.

Cimetidine, a H(2) receptor antagonist, has been reported to improve survival in gastrointestinal cancer patients. These effects have largely been attributed to the enhancing effects of cimetidine on the host's antitumour cell-mediated immune response, such as inhibition of suppressor T lymphocyte activity, stimulation of natural killer cell activity and increase of interleukin-2 production from helper T lymphocytes. We conducted an in vitro study on the effects of cimetidine on differentiation and antigen presenting capacity of monocyte-derived dendritic cells from advanced colorectal cancer patients and normal controls. As a result, an investigation of expression of surface molecules associated with dendritic cells by flow cytometric analyses showed that cimetidine had no enhancing effect on differentiation of dendritic cells from cancer patients and normal controls. An investigation of [(3)H]thymidine incorporation by allogeneic mixed lymphocyte reactions revealed that cimetidine increased the antigen presenting capacity of dendritic cells from both materials. Moreover, a higher antigen presenting capacity was observed in advanced cancer patients compared to normal controls. These effects might be mediated via specific action of cimetidine and not via H(2) receptors because famotidine did not show similar effects. Our results suggest that cimetidine may enhance the host's antitumour cell-mediated immunity by improving the suppressed dendritic cells function of advanced cancer patients

Potential anticancer activity of turmeric (Curcuma longa).

Kuttan R, Bhanumathy P, Nirmala K, et al.

Cancer Lett. 1985 Nov; 29(2):197-202.

Anticancer activity of the rhizomes of turmeric was evaluated in vitro using tissue culture methods and in vivo in mice using Dalton's lymphoma cells grown as ascites form. Turmeric extract inhibited the cell growth in Chinese Hamster Ovary (CHO) cells at a concentration of 0.4 mg/ml and was cytotoxic to lymphocytes and Dalton's lymphoma cells at the same concentration. Cytotoxic effect was found within 30 min at room temperature (30 degrees C). The active constituent was found to be 'curcumin' which showed cytotoxicity to lymphocytes and Dalton's lymphoma cells at a concentration of 4 micrograms/ml. Initial experiments indicated that turmeric extract and curcumin reduced the development of animal tumours

Cellular mechanisms of calcium and vitamin D in the inhibition of colorectal carcinogenesis.

Lamprecht SA, Lipkin M.

Ann N Y Acad Sci. 2001 Dec; 952:73-87.

Convincing evidence is available showing that dietary calcium and vitamin D impede the development of colonic carcinogenesis. The major cellular modes of action of calcium and vitamin D which can contribute to the inhibition of colonic neoplasia are reviewed in this article. These consist of complex series of signaling events induced by the chemopreventive agents acting at various tiers of colonic cell organization

Cancer. p53, guardian of the genome.

Lane DP.

Nature. 1992 Jul 2; 358(6381):15-6.

[Selenium therapy in colorectal tumors?].

Lasch K, Brasel C, Jahn H.

Med Klin (Munich). 1999 Oct 15; 94 Suppl 3:97-100.

BACKGROUND: Is the complementary supplementation of selenium useful in the therapy of colorectal cancer? PATIENTS AND METHODS: Fifty-three patients with primary colorectal cancer received a selenium treatment for 19 days in addition to a complete in-patient rehabilitation cure based on a behavioural approach. A comparative control group consisted of 41 patients. Measured factors were the selenium content in serum and whole blood, GSH-Px activity and TBARS in serum. Both the intake of selenium by nutrition and the patients' life quality were determined additionally on day 1 and 19. The tumor marker CA 19-9 was measured only on day 1. RESULTS: A latent selenium deficiency was observed while gsh-px activity or concentration of TBARS were normal. The selenium status corresponds to the concentration of the tumor marker CA 19-9. The selenium status improves through supplementation, accompanied by a further increase of GSH-Px activity. During supplementation the patients' life quality improves; subjective physical complaints decrease. CONCLUSION: Further research will be necessary on both the dependency of the selenium status on the tumor marker concentration and on the development of the cancer. Optimum GSH-Px activity and individually different responses also need additional investigation. The influence of selenium on the patients' life quality should be investigated in the context of immunomodulation

Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. A case-control study.

Lashner BA, Heidenreich PA, Su GL, et al.

Gastroenterology. 1989 Aug; 97(2):255-9.

Folate deficiency has been associated with dysplasia in human cancer models. Patients with ulcerative colitis commonly have decreased folate levels, which are partially due to sulfasalazine, a competitive inhibitor of folate absorption. To study the effect of folate supplementation on the risk of dysplasia or cancer (neoplasia) in ulcerative colitis, records from 99 patients with pancolitis for greater than 7 yr and enrolled in a surveillance program were reviewed. Thirty-five patients with neoplasia were compared with 64 patients in whom dysplasia was never found to determine the effect of folate supplementation on the rate of development of neoplasia using case-control methodology. At the time of the index colonoscopy, patients with neoplasia were older (43 +/- 11 vs. 39 +/- 12 yr) and had disease of longer duration (20 +/- 8 vs. 15 +/- 7 yr, p less than 0.05). Folate supplementation was associated with a 62% lower incidence of neoplasia compared with individuals not receiving supplementation (odds ratio, 0.38; 95% confidence interval, 0.12-1.20). There was no appreciable change in this effect when models were fit to adjust for sulfasalazine dose, duration of disease, age at symptom onset, prednisone dose, sulfa allergy, sex, race, or family history of colon cancer. The statistical power of the association between folate supplementation and neoplasia was 72%. Correction of risk factors before the development of neoplasia may prevent this serious complication. Pending a larger case-control study, folate supplementation during sulfasalazine administration is recommended to possibly prevent the complication of dysplasia or cancer in ulcerative colitis

The effect of folic acid supplementation on the risk for cancer or dysplasia in ulcerative colitis.

Lashner BA, Provencher KS, Seidner DL, et al.

Gastroenterology. 1997 Jan; 112(1):29-32.

BACKGROUND & AIMS: Two case-control studies have shown that folate may protect against neoplasia in ulcerative colitis. This historical cohort study was performed to better define this association. METHODS: The records of 98 patients with ulcerative colitis who had disease proximal to the splenic flexure for at least 8 years were reviewed. Documented folate use of at least 6 months was deemed a positive exposure. RESULTS: Of the patients, 29.6% developed neoplasia and 40.2% took folate supplements. The adjusted relative risk (RR) of neoplasia for patients taking folate was 0.72 (95% confidence interval [CI], 0.28-1.83). The dose of folate varied with the risk of neoplasia (RR, 0.54 for 1.0 mg folate; RR, 0.76 for 0.4 mg folate in a multivitamin compared with patients taking no folate). Folate use also varied with the degree of dysplasia (RR for cancer, 0.45; RR for high-grade dysplasia, 0.52; RR for low-grade dysplasia, 0.75 compared with patients with no dysplasia) (P = 0.08). CONCLUSIONS: Although not statistically significant, the RR for folate supplementation on the risk of neoplasia is < 1 and shows a dose-response effect, consistent with previous studies. Daily folate supplementation may protect against the development of neoplasia in ulcerative colitis

Molecular analysis on the chemopreventive properties of resveratrol, a plant polyphenol microcomponent.

Latruffe N, Delmas D, Jannin B, et al.

Int J Mol Med. 2002 Dec; 10(6):755-60.

As a plant microcomponent, resveratrol is a polyphenolic compound produced by several species and found especially in Polygonum roots, peanuts seeds, berries and also grape and therefore can be present in human diet or beverages (red wine, for instance). Traditional chinese medicine and more recent epidemiological studies strongly suggested that resveratrol may act as a cancer chemopreventive compound. The biochemical mechanism by which resveratrol inhibits cell proliferation was provided by studies in numerous human cell lines including our work in hepatoblastoma HepG2 and colorectal tumor SW480 cells. The results show that resveratrol strongly inhibits cell proliferation at the micromolar range in a time- and dose-dependent manner. Resveratrol appears to block the cell cycle at the transition S to G2/M since there is no inhibition of [3H]-thymidine incorporation observed, while there is an increase of the cell number in S phase. On the other hand, in order to evaluate if the amount of resveratrol taken up during food or drink consumption is sufficient to ensure in the whole body the in vitro described beneficial effects, we evaluated the ratio between plasmatic level of resveratrol and its cell bioabsorption. Our study reports a higher uptake of resveratrol in the human hepatic derived HepG2 cells than in colorectal derived SW480 cells. In contrast, resveratrol is conjugated in these cells and derivatives are released in large amounts in the cell medium. Based on present knowledge, resveratrol appears to be a promising bioactive natural molecule with potential applications in phytotherapy, pharmacology or in nutriprotection (nutraceutic food) area

Colorectal hepatic metastases: Role of radiofrequency ablation.

Lau TN, Lo RH, Tan BS.

Ann Acad Med Singapore. 2003 Mar; 32(2):212-8.

INTRODUCTION: Radiofrequency ablation (RFA) is a new minimally invasive treatment that has been increasingly used in the treatment of liver metastases. This review aims to outline the principles governing the use of RFA and to examine its role when applied to the management of colorectal liver metastases. METHODS: A Medline search of experimental and clinical studies relating to the use of RFA in the management of colorectal hepatic metastasis was carried out. RESULTS: RFA is currently used as an alternative to surgery in patients with unresectable disease, and sometimes as its companion, allowing patients hitherto considered unsuitable for resection to become surgical candidates. RFA has been shown to be safe and well tolerated, with few major complications and minimal patient discomfort. Although its use is unlikely to achieve cure in such patients, it has a definite role in palliation and relief of symptoms. Long-term data, when these become available, may also show improved survival. However, because RFA is a local ablative therapy, it does not address the progressive and systemic nature of colorectal carcinoma. CONCLUSIONS: RFA is an important alternative/complimentary tool in the management of colorectal hepatic metastases. Combining RFA with surgery or chemotherapy may reduce the incidence of local and systemic relapse

[Neoplasm markers useful for diagnosis and monitoring of colonic neoplasms].

Lawicki S, Mroczko B, Szmitkowski M.

Postepy Hig Med Dosw. 2002; 56(5):617-34.

Serum tumor markers: CEA, CA 19-9, AFP, TPS may be helpful in early diagnosis of colorectal cancer, in the initial assessment of the extent of the disease, and in monitoring of the tumor growth or tumor volume reduction once cancer has been diagnosed and treatment started. Recent studies have focused on a new substances (candidates for tumour markers) of colorectal cancer

DNA methylation and genetic instability in colorectal cancer cells.

Lengauer C, Kinzler KW, Vogelstein B.

Proc Natl Acad Sci U S A. 1997 Mar 18; 94(6):2545-50.

Apparent alterations in DNA methylation have been observed in many cancers, but whether such alterations represent a persistent alteration in the normal methylation process is not known. In this study, we report a striking difference in the expression of exogenously introduced retroviral genes in various colorectal cancer cell lines. Extinguished expression was associated with DNA methylation and could be reversed by treatment with the demethylating agent 5-azacytidine. A striking correlation between genetic instability and methylation capacity suggested that methylation abnormalities may play a role in chromosome segregation processes in cancer cells

The molecular mechanisms for the antitumorigenic effect of curcumin.

Leu TH, Maa MC.

Curr Med Chem Anti -Canc Agents. 2002 May; 2(3):357-70.

Curcumin, an active yellow pigment of turmeric and curry, possesses anti-inflammatory, antioxidative and anticarcinogenic properties. Analysis of its structure revealed the presence of beta-diketone moiety and phenolic hydroxy groups that were believed to contribute to antioxidation. And vanillin, ferulic acid and a dimer of curcumin were identified as the curcumin-derived radical reaction products. In addition to antioxidation, curcumin could also induce apoptosis by targeting mitochondria, affecting p53-related signaling and blocking NF-kappaB activation. To further dissect its anticarcinogenic mechanisms, a number of curcumin targets were identified. These included the aryl hydrocarbon receptor, cytochrome P450, glutathione S-transferase, serine/threonine kinases, transcription factors, cyclooxygenase, ornithine decarboxylase, nitric oxide synthase, matrix metalloproteinases and tyrosine kinases. This review will summarize our current knowledge on how these important proteins are affected by curcumin, and hopefully, may provide a whole picture illustrating how the chemopreventive and antitumorigenic effect of curcumin is achieved

p53, the cellular gatekeeper for growth and division.

Levine AJ.

Cell. 1997 Feb 7; 88(3):323-31.

Studies on the role of some synthetic curcuminoid derivatives in the inhibition of tumour specific angiogenesis.

Leyon PV, Kuttan G.

J Exp Clin Cancer Res. 2003 Mar; 22(1):77-83.

In this study, some of the synthetic curcuminoid derivatives are analyzed for their anti-angiogenic activity. Intraperitoneal administration of the compounds tetrahydrocurcumin (THC), salicyl curcumin (SC) and curcuminIII (C-III) reduced the number of tumour directed capillaries induced by injecting B16F-10 melanoma cells on the ventral side of C57BL/6 mice. THC (14.5 +/- 2.5 capillaries) and SC (16 +/- 2.5 capillaries) were more significant (P < 0.001) than C-III (19 +/- 1.8 capillaries) compared to the untreated control (30.8 +/- 2.1 capillaries). Treatment with these curcuminoids reduced the serum NO as well as TNF-alpha levels of the angiogenesis-induced animals. In vitro NO and TNF-alpha production by the activated MOs were reduced in a concentration dependent manner by the treatment of the curcuminoid compounds

Resveratrol-induced G2 arrest through the inhibition of CDK7 and p34CDC2 kinases in colon carcinoma HT29 cells.

Liang YC, Tsai SH, Chen L, et al.

Biochem Pharmacol. 2003 Apr 1; 65(7):1053-60.

Resveratrol (3,5,4'-trihydroxystilbene), a phytoalexin found in grapes and other food products, has been shown to have cancer chemopreventive activity. However, the mechanism of the anti-carcinogenic activity is not well understood. Here, we offer a possible explanation of its anti-tumor effect. Based on flow cytometric analysis, resveratrol inhibited the proliferation of HT29 colon cancer cells and resulted in their accumulation in the G(2) phase of the cell cycle. Western blot analysis and kinase assays demonstrated that the perturbation of G(2) phase progression by resveratrol was accompanied by the inactivation of p34(CDC2) protein kinase, and an increase in the tyrosine phosphorylated (inactive) form of p34(CDC2). Kinase assays revealed that the reduction of p34(CDC2) activity by resveratrol was mediated through the inhibition of CDK7 kinase activity, while CDC25A phosphatase activity was not affected. In addition, resveratrol-treated cells were shown to have a low level of CDK7 kinase-Thr(161)-phosphorylated p34(CDC2). These results demonstrated that resveratrol induced cell cycle arrest at the G(2) phase through the inhibition of CDK7 kinase activity, suggesting that its anti-tumor activity might occur through the disruption of cell division at the G(2)/M phase

Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals.

Lieberman DA, Prindiville S, Weiss DG, et al.

JAMA. 2003 Dec 10; 290(22):2959-67.

CONTEXT: Knowledge of risk factors for colorectal neoplasia could inform risk reduction strategies for asymptomatic individuals. Few studies have evaluated risk factors for advanced colorectal neoplasia in asymptomatic individuals, compared risk factors between persons with and without polyps, or included most purported risk factors in a multivariate analysis. OBJECTIVE: To determine risk factors associated with advanced colorectal neoplasia in a cohort of asymptomatic persons with complete colonoscopy. DESIGN, SETTING, AND PARTICIPANTS: Prospective, cross-sectional study of 3121 asymptomatic patients aged 50 to 75 years from 13 Veterans Affairs medical centers conducted between February 1994 and January 1997. All participants had complete colonoscopy to determine the prevalence of advanced neoplasia, defined as an adenoma that was 10 mm or more in diameter, a villous adenoma, an adenoma with high-grade dysplasia, or invasive cancer. Variables examined included history of first-degree relative with colorectal cancer, prior cholecystectomy, serum cholesterol level, physical activity, smoking, alcohol use, and dietary factors. MAIN OUTCOME MEASURES: An age-adjusted analysis was performed for each variable to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) associated with having advanced neoplasia compared with having no polyps. We developed a multivariate logistic regression model to identify the most informative risk factors. A secondary analysis examined risk factors for having hyperplastic polyps compared with having no polyps and compared with having advanced neoplasia. RESULTS: Three hundred twenty-nine participants had advanced neoplasia and 1441 had no polyps. In multivariate analyses, we found positive associations for history of a first-degree relative with colorectal cancer (OR, 1.66; 95% CI, 1.16-2.35), current smoking (OR, 1.85; 95% CI, 1.33-2.58), and current moderate to heavy alcohol use (OR, 1.02; 95% CI, 1.01-1.03). Inverse associations were found for cereal fiber intake (OR, 0.95; 95% CI, 0.91-0.99), vitamin D intake (OR, 0.94; 95% CI, 0.90-0.99), and use of nonsteroidal anti-inflammatory drugs (NSAIDs) (OR, 0.66; 95% CI, 0.48-0.91). In the univariate analysis, the inverse association was found with cereal fiber intake greater than 4.2 g/d, vitamin D intake greater than 645 IU/d, and daily use of NSAIDs. Marginal factors included physical activity, daily multivitamin use, and intake of calcium and fat derived from red meat. No association was found for body mass index, prior cholecystectomy, or serum cholesterol level. Three hundred ninety-one patients had hyperplastic polyps as the worst lesion found at colonoscopy. Risk variables were similar to those for patients with no polyps, except that past and current smoking were associated with an increased risk of hyperplastic polyps. CONCLUSIONS: Our data endorse several important risk factors for advanced colonic neoplasia and provide a rationale for prudent risk reduction strategies. Further study is needed to determine if lifestyle changes can moderate the risk of colorectal cancer

Prevalence and incidence of hyperplastic polyps and adenomas in familial colorectal cancer: correlation between the two types of colon polyps.

Liljegren A, Lindblom A, Rotstein S, et al.

Gut. 2003 Aug; 52(8):1140-7.

BACKGROUND AND AIMS: Colorectal adenomas are recognised as precursors of colorectal carcinomas. The significance of hyperplastic (metaplastic) colorectal polyps is unknown. The relationship between hyperplastic polyps and adenomas, and the prevalence and incidence of these lesions were evaluated in individuals predisposed to familial colorectal cancer. METHODS: A total of 299 individuals participating in our surveillance programme during 1990-2000 were retrospectively evaluated. Subjects were classified into three groups: hereditary non-polyposis syndrome (HNPCC) (n=108), hereditary colorectal cancer (HCRC) (n=127), and individuals with empirical risk estimates-two close relatives (TCR) (n=64). Findings from 780 colonoscopies were evaluated regarding prevalence and incidence of hyperplastic polyps and adenomas. Correlations between hyperplastic polyps and adenomas were calculated by Pearson correlation. RESULTS: In total, 292 hyperplastic polyps and 186 adenomas were observed in 98 and 90 individuals, respectively. A positive correlation was found between the numbers of hyperplastic polyps and adenomas (r=0.40; p<0.001). Correlations between adenomas and hyperplastic polyps were similar in the three groups. The risk of detecting new hyperplastic polyps (odds ratio 5.41) or adenomas (OR 2.56) increased significantly when there was a positive finding at first colonoscopy. CONCLUSION: Hyperplastic polyps as well as adenomas may identify individuals with a high risk of colorectal cancer. This information is important when these individuals are selected and included in tailored surveillance programmes

Calcium supplementation modifies the relative amounts of bile acids in bile and affects key aspects of human colon physiology.

Lupton JR, Steinbach G, Chang WC, et al.

J Nutr. 1996 May; 126(5):1421-8.

Use of calcium supplements has increased dramatically in recent years yet little is known about the effect of calcium supplementation on colon physiology. We supplemented 22 individuals with a history of resected adenocarcinoma of the colon, but currently free of cancer, with 2000 or 3000 mg calcium for 16 wk. The effects of supplementation on duodenal bile acids and important fecal characteristics including total fecal output, wet and dry weight, pH, bile acids (in solids and in fecal water), and concentrations and total excretion of calcium, magnesium, phosphates (organic and inorganic), unesterified fatty acids and total fat were determined. Calcium supplementation significantly decreased the proportion of water in the stool (P = 0.03), doubled fecal excretion of calcium (P = 0.006), and increased excretion of organic phosphate (P = 0.035) but not magnesium. Calcium supplementation significantly decreased the proportion of chenodeoxycholic acid in bile (P = 0.007) and decreased the ratio of lithocholate to deoxycholate in feces (P = 0.06). The concentration of primary bile acids in fecal water decreased after 16 wk Ca supplementation. Together with other reports of a "healthier" bile acid profile with respect to colon cancer when changes such as those observed in this study were achieved, these results suggest a protective effect of calcium supplementation against this disease

Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3.

Ma J, Pollak MN, Giovannucci E, et al.

J Natl Cancer Inst. 1999 Apr 7; 91(7):620-5.

BACKGROUND: Insulin-like growth factor-I (IGF-I) is a potent mitogen for normal and neoplastic cells, whereas IGF-binding protein-3 (IGFBP-3) inhibits cell growth in many experimental systems. Acromegalics, who have abnormally high levels of growth hormone and IGF-I, have higher rates of colorectal cancer. We therefore examined associations of plasma levels of IGF-I and IGFBP-3 with the risk of colorectal cancer in a prospective case-control study nested in the Physicians' Health Study. METHODS: Plasma samples were collected at baseline from 14916 men without diagnosed cancer. IGF-I, IGF-II, and IGFBP-3 were assayed among 193 men later diagnosed with colorectal cancer during 14 years of follow-up and among 318 age- and smoking-matched control subjects. All P values are two-sided. RESULTS: IGFBP-3 levels correlated with IGF-I levels (r=.64) and with IGF-II levels (r=.90). After controlling for IGFBP-3, age, smoking, body mass index (weight in kg/[height in m]2), and alcohol intake, men in the highest quintile for IGF-I had an increased risk of colorectal cancer compared with men in the lowest quintile (relative risk [RR]=2.51; 95% confidence interval [CI]=1.15-5.46; P for trend = .02). After controlling for IGF-I and other covariates, men with higher IGFBP-3 had a lower risk (RR=0.28; 95% CI=0.12-0.66; P for trend = .005, comparing extreme quintiles). The associations were consistent during the first and the second 7-year follow-up intervals and among younger and older men. IGF-II was not associated with risk. CONCLUSIONS: Our findings suggest that circulating IGF-I and IGFBP-3 are related to future risk of colorectal cancer

Role of Bax in resveratrol-induced apoptosis of colorectal carcinoma cells.

Mahyar-Roemer M, Kohler H, Roemer K.

BMC Cancer. 2002 Oct 17; 2(1):27.

BACKGROUND: The natural plant polyphenol resveratrol present in some foods including grapes, wine, and peanuts, has been implicated in the inhibition, delay, and reversion of cellular events associated with heart diseases and tumorigenesis. Recent work has suggested that the cancer chemoprotective effect of the compound is primarily linked to its ability to induce cell division cycle arrest and apoptosis, the latter possibly through the activation of pro-apoptotic proteins such as Bax. METHODS: The expression, subcellular localization, and importance of Bax for resveratrol-provoked apoptosis were assessed in human HCT116 colon carcinoma cells and derivatives with both bax alleles inactivated. RESULTS: Low to moderate concentrations of resveratrol induced co-localization of cellular Bax protein with mitochondria, collapse of the mitochondrial membrane potential, activation of caspases 3 and 9, and finally, apoptosis. In the absence of Bax, membrane potential collapse was delayed, and apoptosis was reduced but not absent. Resveratrol inhibited the formation of colonies by both HCT116 and HCT116 bax -/- cells. CONCLUSION: Resveratrol at physiological doses can induce a Bax-mediated and a Bax-independent mitochondrial apoptosis. Both can limit the ability of the cells to form colonies

Vitamin D3 is a potent inhibitor of tumor cell-induced angiogenesis.

Majewski S, Skopinska M, Marczak M, et al.

J Investig Dermatol Symp Proc. 1996 Apr; 1(1):97-101.

Vitamin D3 derivative 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) exerts various biological effects in cells that possess vitamin D3 receptor (VDR), including enhancement of cell differentiation and inhibition of cell proliferation. These activities of 1,25(OH)2D3 might be responsible for its anti-neoplastic effects, as shown in various experimental systems. The aim of this study was to compare the anti-angiogenic activity of 1,25(OH)2D3, retinoids, and interleukin-12 (IL-12) in an experimental tumor cell-induced angiogenesis assay in mice. Tumor cell-induced angiogenesis assay was performed in x-ray immunosuppressed BALB/c mice by intradermal injections of human tumor cell lines of different origin. The injections resulted within 3 d in a local formation of new blood vessels, and the intensity of angiogenesis correlated with the number of injected cells. Systemic treatment of the mouse recipients with 1,25(OH)2D3 significantly decreased angiogenesis, comparable to the effect of retinoids (all-trans retinoic acid [RA], 9-cis RA and 13-cis RA) and of IL-12. In vitro preincubation of the cells with all compounds (except IL-12) led to the inhibition of their angiogenic capability in vivo. Moreover, combination of 1,25(OH)2D3 and retinoids resulted in a synergistic inhibition of angiogenesis. The results strongly suggest that anti-angiogenic compounds with relatively low toxicity (e.g., 1,25(OH)2D3, retinoids, and IL-12) and their combinations could be beneficial in the treatment of some angiogenesis-associated malignancies

Faecal urobilinogen levels and pH of stools in population groups with different incidence of cancer of the colon, and their possible role in its aetiology.

Malhotra SL.

J R Soc Med. 1982 Sep; 75(9):709-14.

Mean faecal urobilinogen levels and the pH of stools were both found to be higher in subjects from a population group at high risk of developing cancer of the colon than in subjects matched for age, sex and socioeconomic status from a low-risk population group. An alkaline reaction of the colon contents seems to have a tumorigenic effect by a direct action on the mucus of the mucous cells. An acidic reaction, on the other hand, appears to be protective. These differences are dependent on the patterns of diet and manner of eating. Proper mastication of food, roughage, cellulose and vegetable fibre, and short-chain fatty acids of milk and fermented milk products in the diet appear to be protective

A short-term dietary supplementation of high doses of vitamin E increases T helper 1 cytokine production in patients with advanced colorectal cancer.

Malmberg KJ, Lenkei R, Petersson M, et al.

Clin Cancer Res. 2002 Jun; 8(6):1772-8.

PURPOSE: Patients with advanced cancer exhibit multifaceted defects in their immune capacity, which are likely to contribute to an increased susceptibility to infections and disease progression and to constitute a barrier to immunotherapeutic interventions. A chronic inflammatory condition associated with increased oxidative stress has been suggested as one of the responsible mechanisms behind the tumor-induced immune suppression. We, therefore, speculated that supplementation with the antioxidant vitamin E could enhance the immune functions in patients with advanced cancer. EXPERIMENTAL DESIGN: This hypothesis was here tested in twelve patients with colorectal cancer (Dukes' C and D) who, prior to intervention with chemo- or radiotherapy, received a daily dose of 750 mg of vitamin E during a period of 2 weeks. RESULTS: Short-term supplementation with high doses of dietary vitamin E leads to increased CD4:CD8 ratios and to enhanced capacity by their T cells to produce the T helper 1 cytokines interleukin 2 and IFN-gamma. In 10 of 12 patients, an increase of 10% or more (average, 22%) in the number of T cells producing interleukin 2 was seen after 2 weeks of vitamin E supplementation, as compared with peripheral blood monocyte samples taken before treatment (P = 0.02). Interestingly, there seemed to be a more pronounced stimulatory effect by vitamin E on naive (CD45RA(+)) T helper cells as compared with T cells with a memory/activated phenotype. CONCLUSIONS: Dietary vitamin E may be used to improve the immune functions in patients with advanced cancer, as a supplement to more specific immune interventions

Serum values of proinflammatory cytokines are inversely correlated with serum leptin levels in patients with advanced stage cancer at different sites.

Mantovani G, Maccio A, Madeddu C, et al.

J Mol Med. 2001 Jul; 79(7):406-14.

Leptin is a recently identified hormone produced by the adipocyte ob gene which acts as a negative feedback signal critical to the normal control of food intake and body weight. A number of proinflammatory cytokines, such as interleukin 6, tumor necrosis factor alpha, and interferon gamma, have been proposed as mediators of cancer cachexia; these data suggest that abnormalities in leptin production/release or in its feedback mechanism play a role in cancer patients. We therefore studied the relationship between serum leptin and serum cytokines interleukin 6 and tumor necrosis factor alpha levels in advanced-stage cancer patients. Twenty-nine advanced stage cancer patients (all but one stage IV) with tumors at various sites were included in the study. A direct correlation between body mass index and serum leptin levels was found both in cancer patients and in healthy individuals. The serum levels of interleukin 6 were significantly higher in cancer patients than in healthy individuals. In cancer patients an inverse correlation was found between serum levels of leptin and proinflammatory cytokines. There was an inverse correlation between the Eastern Cooperative Oncology Group performance status scale and serum levels of leptin. Regarding survival, patients with very high serum levels of proinflammatory cytokines and very low levels of leptin had very short survival. Although obtained in a cancer patient population not overtly cachectic, our results provide further evidence that a simple dysregulation of leptin production and/or release cannot be involved in cancer-associated pathophysiological changes leading to cachexia

Screening and surveillance for colorectal carcinoma.

Markowitz AJ, Winawer SJ.

Hematol Oncol Clin North Am. 1997 Aug; 11(4):579-608.

Screening and surveillance examinations are effective in lowering colorectal cancer risk. Screening tests have been demonstrated to reduce colorectal cancer mortality. Colonoscopic removal of adenomatous polyps has been determined to reduce colorectal cancer incidence. High-risk individuals and their family members should be identified and offered more aggressive recommendations for appropriate screening and surveillance guidelines. Colorectal cancer screening strategies are in an acceptable range of cost effectiveness

Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives.

Marra G, Boland CR.

J Natl Cancer Inst. 1995 Aug 2; 87(15):1114-25.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by the occurrence within a family of multiple cases of colorectal cancer in the absence of gastrointestinal polyposis. The prevalence of this syndrome is not yet clear, but it may account for 1%-5% of all colorectal cancers. Prior to the identification of the genetic basis of this syndrome, the disease was recognized by the familial aggregation of colorectal cancers that had an early age of onset, an excess of proximally located, and often multiple, primary tumors, and an excess occurrence of cancers in certain other organs. The recent description of an abnormality called "microsatellite instability," present in almost all cancers from HNPCC patients and in about 12%-15% of sporadic cases, led to a series of discoveries that linked this type of genomic instability to a defect in the DNA mismatch repair (MMR) system. Independent investigators have identified four HNPCC genes: hMSH2 (a homologue of the prokaryotic DNA MMR gene MutS) and hMLH1, hPMS1, and hPMS2 (all homologues of the prokaryotic DNA MMR gene MutL). Mutations in each of the four genes have been found in the germline cells of HNPCC families. A major target for research in this area is the development of clinically practical screening tests for the genetic carrier state of HNPCC

Calcium, vitamin D, and the occurrence of colorectal cancer among women.

Martinez ME, Giovannucci EL, Colditz GA, et al.

J Natl Cancer Inst. 1996 Oct 2; 88(19):1375-82.

BACKGROUND: Despite evidence from animal studies for a protective effect of higher calcium and possibly vitamin D intake against colorectal cancer, epidemiologic studies have been inconclusive. PURPOSE: We investigated the associations between the intake of calcium and vitamin D and the occurrence of colorectal cancer. METHODS: In a prospective study, 89 448 female registered nurses who were free of cancer responded to a mailed, semiquantitative food-frequency questionnaire in 1980; dietary information was updated in 1984 and 1986. Through 1992, 501 incident cases of colorectal cancer (396 colon and 105 rectal cancers) were documented. As measures of exposure, we used nutrient intake in 1980 and also two measures of long-term intake on the basis of the three questionnaires: the average of intakes from the three questionnaires and consistent intakes, which were defined as high if women were in the upper tertile on all questionnaires and low if they were in the lower tertile on all questionnaires. To further characterize long-term intake, we conducted analyses excluding women who reported a change in their consumption of milk (primary source of calcium and vitamin D) in the 10 years prior to 1980. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using the lowest quintile of intake as a reference. The Mantel extension test was used to evaluate linear trends across the categories of nutrient intake. In multivariate analyses, the trends were tested with use of the medians of the intake as a continuous variable in the logistic model. The P values for the trends were two-sided. RESULTS: On the basis of the data from the 1980 questionnaire alone, the multivariate RR for colorectal cancer for women in the upper versus the lower quintile were 0.80 (95% CI = 0.60-1.07) for dietary calcium, 0.84 (95% CI = 0.63-1.13) for dietary vitamin D (from foods only), and 0.88 (95% CI = 0.66-1.16) for total vitamin D (from foods and supplements). After the exclusion of women who reported a change in their milk intake, the RRs for colorectal cancer for the highest versus the lowest categories of average intake were 0.74 (95% CI = 0.36-1.50) for dietary calcium, 0.72 (95% CI = 0.34-1.54) for dietary vitamin D, and 0.42 (95% CI = 0.19-0.91) for total vitamin D. The corresponding RRs for the consistency analyses were 0.70 (95% CI = 0.35-1.39) for dietary calcium, 0.59 (95% CI = 0.30- 1.16) for dietary vitamin D, and 0.33 (95% CI = 0.16-0.70) for total vitamin D. CONCLUSIONS: These findings do not support a substantial inverse association between calcium intake and risk of colorectal cancer, but an inverse association between intake of total vitamin D and risk of colorectal cancer was suggested. IMPLICATIONS: Available evidence does not warrant an increase in calcium intake to prevent colon cancer, but longer-term studies of both calcium and especially vitamin D in relation to colorectal cancer risk are needed

Physical activity, body mass index, and prostaglandin E2 levels in rectal mucosa.

Martinez ME, Heddens D, Earnest DL, et al.

J Natl Cancer Inst. 1999 Jun 2; 91(11):950-3.

BACKGROUND: Evidence suggests a relationship between prostaglandin levels in colonic mucosa and risk of colon cancer. Physical inactivity and a higher body mass index (BMI; weight in kilograms divided by [height in meters]2) have been consistently shown to increase risk of this cancer. We investigated whether higher levels of leisure-time physical activity or a lower BMI was associated with lower concentrations of prostaglandin E2 (PGE2) in rectal mucosa. METHODS: This study was conducted in 41 men and 22 women, 42-78 years of age, with a history of polyps, who participated in a randomized clinical trial testing the effects of piroxicam on rectal mucosal PGE2 levels. An [125I]PGE2 radioimmunoassay kit was used to determine PGE2 levels in samples of extracted rectal mucosa collected before randomization. Leisure-time physical activity was assessed through a self-administered questionnaire collected at baseline. The reported time spent at each activity per week was multiplied by its typical energy expenditure, expressed in metabolic equivalents (METs), to yield a MET-hours per week score. A repeated measures model was used to assess the effect of BMI and physical activity as predictors of PGE2 concentration. All statistical tests were two-sided. RESULTS: After adjustment for age, a higher BMI was associated with higher PGE2 levels (P = .001). A higher level of leisure-time physical activity was inversely associated with PGE2 concentration (P<.03). An increase in BMI from 24.2 to 28.8 kg/m2 was associated with a 27% increase in PGE2. An increase in activity level from 5.2 to 27.7 MET-hours per week was associated with a 28% decrease in PGE2. CONCLUSIONS: Physical activity and obesity may alter the risk of colon cancer through their effects on PGE2 synthesis

Calcium, vitamin D, and risk of adenoma recurrence (United States).

Martinez ME, Marshall JR, Sampliner R, et al.

Cancer Causes Control. 2002 Apr; 13(3):213-20.

OBJECTIVE: Few data exist regarding the association between calcium intake and adenoma recurrence, and no data exist for vitamin D. We investigated the role of dietary and supplemental sources of calcium and vitamin D in the etiology of adenoma recurrence. METHODS: Analyses were conducted among 1304 male and female participants in the Wheat Bran Fiber (WBF) trial of adenoma recurrence. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In the fully adjusted multivariate model, the OR for participants with dietary calcium intake above 1,068 versus those with intake below 698 mg/day was 0.56 (95% CI = 0.39-0.80; p-trend = 0.007). Calcium supplementation at doses above 200 mg/day did not affect risk of recurrence. Although a borderline inverse association between dietary vitamin D and recurrence was observed after adjustment for age and gender, the association weakened in the fully adjusted model (OR = 0.78 for individuals in the upper compared to the lower quartile; 95% CI = 0.54-1.13). No association was shown for supplemental sources of vitamin D. CONCLUSIONS: Results of this study indicate that a higher intake of calcium decreases the risk of adenoma recurrence by approximately 45%, whereas vitamin D has no significant effect on recurrence rates

Nutritional chemoprevention of colon cancer.

Mason JB.

Semin Gastrointest Dis. 2002 Jul; 13(3):143-53.

Evidence emerging from many different types of experimental designs continues to support the concept that dietary habits, and nutritional status, play important roles in determining the risk of developing colorectal cancer. Overall, a diet habitually high in fresh fruits and vegetables, modest in calories and alcohol, and low in red meat and animal fat is cancer protective. This field of investigation is nevertheless very confusing, particularly because longstanding hypotheses, such as the presumed protective effects of fruits, vegetables, and fiber, have recently been challenged by well-designed prospective trials. The search for individual components in the diet that convey protection continues: calcium, folate, and selenium are the leading candidates in this regard. There is also growing interest in other plant-based compounds, so-called phytochemicals, although our understanding of their effects is quite rudimentary at present. However, regardless of the constituent components of the diet, evidence continues to accrue that ingesting a sensible amount of calories and maintaining a desirable weight also play important roles in prevention of this cancer. Although the inconsistencies in this field make it tempting to minimize its import, there is little question that diet has a major impact on colorectal cancer risk; diligent attention to the rigorous conduct of studies and their interpretation will likely clarify these relationships over the next decade, much to the benefit of public health

Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells.

Matsumoto S, Imaeda Y, Umemoto S, et al.

Br J Cancer. 2002 Jan 21; 86(2):161-7.

Cimetidine has been shown to have beneficial effects in colorectal cancer patients. In this study, a total of 64 colorectal cancer patients who received curative operation were examined for the effects of cimetidine treatment on survival and recurrence. The cimetidine group was given 800 mg day(-1) of cimetidine orally together with 200 mg day(-1) of 5-fluorouracil, while the control group received 5-fluorouracil alone. The treatment was initiated 2 weeks after the operation and terminated after 1 year. Robust beneficial effects of cimetidine were noted: the 10-year survival rate of the cimetidine group was 84.6% whereas that of control group was 49.8% (P<0.0001). According to our previous observations that cimetidine blocked the expression of E-selectin on vascular endothelium and inhibited the adhesion of cancer cells to the endothelium, we have further stratified the patients according to the expression levels of sialyl Lewis antigens X (sL(x)) and A (sL(a)). We found that cimetidine treatment was particularly effective in patients whose tumour had higher sL(x) and sL(a) antigen levels. For example, the 10-year cumulative survival rate of the cimetidine group with higher CSLEX staining, recognizing sL(x), of tumours was 95.5%, whereas that of control group was 35.1% (P=0.0001). In contrast, in the group of patients with no or low levels CSLEX staining, cimetidine did not show significant beneficial effect (the 10-year survival rate of the cimetidine group was 70.0% and that of control group was 85.7% (P=n.s.)). These results clearly indicate that cimetidine treatment dramatically improved survival in colorectal cancer patients with tumour cells expressing high levels of sL(x) and sL(a)

CA 125: a clinically useful tumor marker in the management of colorectal carcinoma metastatic to the liver in patients with normal carcinoembryonic antigen.

Mavligit GM, Estrov Z.

Am J Clin Oncol. 2000 Apr; 23(2):213-5.

Two patients with colon carcinoma metastatic to the liver had normal plasma carcinoembryonic antigen (CEA) levels (<1.0 ng/ml) but elevated CA 125 levels. Treatment of the metastatic disease with chemotherapy, plus surgery in one case, led to declines in the CA 125 levels. These decreases were associated with tumor regression, as confirmed by clinical and radiologic evidence. These findings lead us to conclude that the measurement of CA 125 for patients with normal CEA levels is useful in the management of colorectal carcinoma

Fish oil may impede tumour angiogenesis and invasiveness by down-regulating protein kinase C and modulating eicosanoid production.

McCarty MF.

Med Hypotheses. 1996 Feb; 46(2):107-15.

Inhibition of angiogenesis shows considerable promise as a strategy for treating solid malignancies. Induction of collagenase by protein kinase C plays an important role in the angiogenic process as well as in metastasis. Lipoxygenase products are required for endothelial cell mitosis, and also promote collagenase production. By down-regulating hormonal activation of protein kinase C and modulating eicosanoid metabolism, ingestion of omega-3-rich fish oils may impede angiogenesis and reduce tumor invasiveness-thus rationalizing the growth-retardant and anti-metastatic effects of fish oil feeding almost invariably seen in animal tumour models. Certain other anti-inflammatory agents-including cromolyn (an inhibitor of protein kinase C activation) and gamma-linolenic acid (which indirectly inhibits lipoxygenase) may have analogous tumour-retardant activity. Clinical application of supplemental fish oil in cancer therapy is long overdue

Assessment of past diet in epidemiologic studies.

McKeown-Eyssen GE, Yeung KS, Bright-See E.

Am J Epidemiol. 1986 Jul; 124(1):94-103.

The reproducibility of recall of diet was examined for 44 men in Toronto, Ontario, Canada, by comparing estimates of consumption obtained from a dietary questionnaire in 1982 with estimates of consumption made by recalling the original diet at an interview conducted one year later in 1983. Estimates of average consumption obtained by recall were significantly lower than those originally reported for most foods and nutrients, but the magnitude of the differences was never greater than 20% of the original estimate. Correlations between individuals' levels of consumption were greater than 0.7 for nine of the 13 foods and nutrients studied. Current diet, assessed from two-day food records, was also associated with consumption originally reported for some nutrients. Fecal levels of hemicellulose were associated with fiber consumption originally reported and with current fiber consumption, and urine levels of 3-methylhistidine were associated with past meat consumption. The best prediction of past consumption of fiber and fat, however, was obtained from the recalled diet. No significant additional contribution to the prediction was made from estimates of current consumption or from biochemical measures

Receptors for histamine can be detected on the surface of selected leukocytes.

Melmon KL, Bourne HR, Weinstein J, et al.

Science. 1972 Aug 25; 177(50):707-9.

Controlled release of TGF-beta1 impedes rat colon carcinogenesis in vivo.

Mikhailowski R, Shpitz B, Polak-Charcon S, et al.

Int J Cancer. 1998 Nov 23; 78(5):618-23.

Transforming growth factor beta1 (TGF-beta1) is a cytokine known to play a key role in the control of cell growth. TGF-beta1 potently inhibits the proliferation of human and rodent-derived epithelial cells. Colonic precancerous and moderately differentiated cancer cells are responsive to TGF-beta1, whereas malignant colon cancer cells are resistant to the inhibitory action of the cytokine. These observations have been derived exclusively from in vitro studies. Therefore, the main aim of our study was to determine whether TGF-beta1 exerts a growth-restraining action on colon carcinogenesis in vivo. TGF-beta1 was sequestered into ethylene acetate copolymer matrices and "loaded" preparations were implanted intraperitoneally (i.p.) in rats. One week later, the animals were treated with dimethylhydrazine (DMH), a colon procarcinogen. Empty matrices devoid of TGF-beta1 but containing bovine serum albumin (BSA) carrier served as the appropriate control preparations. The number of aberrant crypt foci (ACF), considered to be preneoplastic lesions of the colon, was scored. Tumor formation and size were assessed at the appropriate times. TGF-beta1 released in a sustained manner from copolymer matrices: (i) markedly inhibited colonic ACF formation and the number of aberrant crypts and (ii) significantly reduced colonic tumor formation and size

Serum levels of selenium, manganese, copper, and iron in colorectal cancer patients.

Milde D, Novak O, Stu k, V, et al.

Biol Trace Elem Res. 2001 Feb; 79(2):107-14.

This article describes a study in which four trace elements (Se, Mn, Cu, and Fe) were analyzed in the blood serum of the patients with colorectal cancer from the Moravian region of the Czech Republic. Atomic absorption spectrometry with graphite furnace atomization was used for analysis of selenium and manganese and with flame atomization for analysis of copper and iron. The observed serum concentrations in adenocarcinoma colorectal patients of selenium were significantly lower (41:8 +/- 11.6 microg/L) and those of manganese (16.3 +/- 4.5 microg/L) and iron (2.89 +/- 1.23 mg/L) were significantly higher as compared to the age-matched control group. Copper serum content (0.95 +/- 0.28 mg/L) did not significantly differ as compared to healthy population

Resectable adenocarcinoma of the rectosigmoid and rectum. II. The influence of blood vessel invasion.

Minsky BD, Mies C, Recht A, et al.

Cancer. 1988 Apr 1; 61(7):1417-24.

Several series have examined the influence of blood vessel invasion (BVI) by tumor on survival of patients with colorectal cancer; however, little data are available regarding its influence on patterns of failure. In an effort to determine the influence of BVI on the patterns of failure and survival in rectosigmoid and rectal cancer, a retrospective review of 168 patients who underwent potentially curative surgery at the New England Deaconess Hospital was performed. In patients who had tumors with extramural BVI, there was a significant decrease in five-year actuarial survival compared with patients who had tumors with intramural BVI or were BVI-negative (BVI-). When the intramural and extramural types of BVI were combined, no significant impact was noted on the patterns of failure or survival in patients with BVI+ versus those with BVI- tumors. In contrast, the presence of lymphatic vessel invasion was found to significantly decrease survival. By using a proportional hazards analysis, it was found that BVI was not an independent prognostic variable. Therefore, the use of BVI alone is not recommended for selecting patients with rectosigmoid and rectal cancer who may benefit from adjuvant therapy

Resectable adenocarcinoma of the rectosigmoid and rectum. I. Patterns of failure and survival.

Minsky BD, Mies C, Recht A, et al.

Cancer. 1988 Apr 1; 61(7):1408-16.

In an effort to determine the patterns of failure and survival of rectosigmoid and rectal cancer, a retrospective review of 168 patients who underwent potentially curative surgery at the New England Deaconess Hospital was performed. The 5-year actuarial survival for the entire group was 67%. Survival rates decreased with increasing penetration of the bowel wall by tumor and the presence of lymph node metastasis, but only the latter reached statistical significance. Those patients who underwent an abdominoperineal resection also experienced a significant decrease in survival compared to a low anterior resection. Patterns of failure, expressed as the actuarial incidence of first failure at 5 years, were examined by stage. With the exception of stages B3 and C3, there was a trend towards increased abdominal, distant, and total failure with increasing bowel wall penetration by tumor. A similar trend was seen in local failure in those patients with positive nodes. Knowledge of these data may help identify those patients who may benefit most from adjuvant therapy

Potentially curative surgery of colon cancer: patterns of failure and survival.

Minsky BD, Mies C, Rich TA, et al.

J Clin Oncol. 1988 Jan; 6(1):106-18.

In an effort to determine the patterns of failure and survival of colon cancer, a retrospective review of 294 patients who underwent potentially curative surgery at the New England Deaconess Hospital (NEDH) was performed. For the entire group, the 5-year crude survival rate was 68% and the actuarial rate was 80%. Survival decreased with increasing bowel wall penetration by tumor and the presence of lymph node metastasis. Although survival varied with the tumor site, none of the differences was statistically significant. Other variables, including the grade of adenocarcinoma, size, and the type of surgery had a significant impact on survival. Patterns of failure, expressed as the actuarial incidence of first diagnosed failure at 5 years, were examined by stage and site. There was a trend toward increased failure with increasing bowel wall penetration by tumor and the presence of lymph node metastasis. Abdominal failure, either as the only site or as a component of failure, was the most common type of failure. When compared by site, patients with cecal carcinoma had a significantly lower incidence of local and distant failure than patients with disease in other selected sites. No differences in patterns of failure were seen in patients with carcinomas in the mobile sections of the colon compared with those who had disease arising in the nonmobile sections of the colon. These data may be useful in identifying those patients who might benefit most from adjuvant therapy

Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase B.

Mohan R, Sivak J, Ashton P, et al.

J Biol Chem. 2000 Apr 7; 275(14):10405-12.

We have studied mechanisms controlling activation of the gelatinase B gene (matrix metalloproteinase-9) by fibroblast growth factor-2 (FGF-2) during angiogenesis, and the effects of the natural product curcuminoids on this process. Using a transgenic mouse (line 3445) harboring a gelatinase B promoter/lacZ fusion gene, we demonstrate FGF-2 stimulation of reporter gene expression in endothelial cells of invading neocapillaries in the corneal micropocket assay. Using cultured corneal cells, we show that FGF-2 stimulates DNA binding activity of transcription factor AP-1 but not NF-kappaB and that AP-1 stimulation is inhibited by curcuminoids. We further show that induction of gelatinase B transcriptional promoter activity in response to FGF-2 is dependent on AP-1 but not NF-kappaB response elements and that promoter activity is also inhibited by curcuminoids. In rabbit corneas, the angiogenic response induced by implantation of an FGF-2 pellet is inhibited by the co-implantation of a curcuminoid pellet, and this correlates with inhibition of endogenous gelatinase B expression induced by FGF-2. Angiostatic efficacy in the cornea is also observed when curcuminoids are provided to mice in the diet. Our findings provide evidence that curcuminoids target the FGF-2 angiogenic signaling pathway and inhibit expression of gelatinase B in the angiogenic process

A protective role of dietary vitamin D3 in rat colon carcinogenesis.

Mokady E, Schwartz B, Shany S, et al.

Nutr Cancer. 2000; 38(1):65-73.

The aim of the present work was to gain insight into a putative anticancer effect of dietary vitamin D3 (cholecalciferol) in a rat model of colon carcinogenesis. Male rats were assigned to three different dietary groups. The dietary regimens were based on a standard murine-defined diet (AIN-76A) or a stress diet containing 20% fat, reduced Ca2+ concentration, a high phosphorus-to-Ca2+ ratio, and either low or high vitamin D3 content. Colorectal cancer was induced by administration of the procarcinogen 1,2-dimethylhydrazine (DMH). Blood Ca2+, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], and 25-hydroxyvitamin D3 [25(OH)D3] levels were measured in DMH-treated rats and in respective weight- and age-matched dietary control groups. Colonic epithelial proliferation was assessed by determining thymidine kinase (TK) activity, bromodeoxyuridine (BrdUrd) incorporation into crypt cell DNA, and the mean labeling index along the colonic crypt continuum. Maintenance of rats on the stress diet either unmodified or supplemented with vitamin D3 in the absence of carcinogen treatment provoked a time-dependent rise in colonic TK activity and hyperproliferation of colonic epithelium. DMH treatment of rats maintained on the standard diet caused a marked increase in the proliferative indexes of colonic epithelium and in expansion of the crypt proliferative compartment. TK activity and the crypt mitotic zone were significantly augmented in the animal group fed the stress diet. Supplementary vitamin D3 abrogated the stress diet-enhanced colonic responses to the carcinogenic insult. Colon tumor multiplicity was fourfold higher in animals fed the stress diet than in animals maintained on a standard diet. The marked rise in colonic tumor multiplicity and adenocarcinoma incidence in rats fed the stress diet was obliterated by supplemental dietary vitamin D3. Cumulatively, the present results indicate that dietary vitamin D3 impedes the neoplastic process in murine large intestine and strengthen the view that inappropriate changes in dietary components and micronutrients are contributory determinants of colorectal cancer

Curcumin induced modulation of cell cycle and apoptosis in gastric and colon cancer cells.

Moragoda L, Jaszewski R, Majumdar AP.

Anticancer Res. 2001 Mar; 21(2A):873-8.

We have investigated the chemopreventive role of curcumin in gastrointestinal cancers by studying the regulation of proliferation and apoptosis in gastric (KATO-III) and colon (HCT-116) cancer cells. Curcumin inhibited cell proliferation and induced G2/M arrest in HCT-116 cells. Investigation of the levels of cyclins E, D and B by immunoblot analysis showed cyclin B level was unaffected, whereas cyclin D and E levels declined with curcumin in both cell lines. Investigation of cyclin-dependent kinases, Cdk2 and Cdc2, showed activity of Cdc2, but not Cdk2, increased markedly in response to curcumin. In both cell lines, immunoblot analysis indicated that curcumin caused induction of apoptosis as evidenced by cleavage of PARP, caspase-3, and reduction in Bcl-XL levels. Curcumin also stimulated the activity of caspase-8, which initiates Fas signalling pathway of apoptosis. Curcumin therefore appears to exert its anticarcinogenic properties by inhibiting proliferation and inducing apoptosis in certain gastric and colon cancer cells

Epidemiological and clinical aspects of nonsteroidal anti-inflammatory drugs and cancer risks.

Moran EM.

J Environ Pathol Toxicol Oncol. 2002; 21(2):193-201.

It is well known that about 70% of cancer cases are due to environmental, dietary, or lifestyle factors. Accordingly, these cases maybe avoided by appropriate modifications. In addition, active chemoprevention has become a major interventional approach following the epidemiological observation of a beneficial effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in colon cancer prevention. This is chiefly due to the inhibition of the cyclooxygenase (COX) enzymes. The COX enzymatic system includes two isoenzymes, COX-1 and COX-2, that convert arachidonic acid to prostaglandins. COX-1 is constitutively expressed and synthesizes cytoprotective prostaglandins in the gastrointestinal tract. COX-2 is inducible by the oncogenes ras and scr and other cytokines; it is overexpressed in human cancer cells in which it stimulates cellular division and angiogenesis and inhibits apoptosis. NSAIDs restore apoptosis and decrease tumor mitogenesis and angiogenesis. Most cancer cells have been found to exhibit overexpression of COX-2. Epidemiological studies showed a lower risk of developing cancer of the colon, breast, esophagus, and stomach following the ingestion of NSAIDs. The use of NSAIDs in low dose was associated with a statistically significant decrease in the risk of adenomatous polyps and of overt colon cancer. The regressive effects of sulindac on foci of aberrant crypts in the colon (considered to be precursors of adenoma), and on adenocarcinoma of the colon, are of particular interest because this NSAID does not have an inhibitory effect on COX. This may support the view that the antineoplastic effect of NSAIDs may also be due to a mechanism other than COX-2 inhibition. In breast cancer, large cohort studies reported a 40 to 50% reduced risk of developing cancer, a smaller size of the primary tumor, and a reduction in the number of involved axillary lymph nodes. Similar findings have been reported in the esophagus and stomach, but not in gastric cardia adenocarcinoma. The recent development of selective COX-2 inhibitors resulted in better clinical tolerance than that associated with NSAIDs in general, with the absence of gastrointestinal side effects known to occur after the inhibition of COX-1. Encouraging results have been obtained with these new agents in familial adenomatous polyposis, colon, breast, and prostate cancer

Inverse mRNA expression of the selenocysteine-containing proteins GI-GPx and SeP in colorectal adenomas compared with adjacent normal mucosa.

Mork H, Al Taie OH, Bahr K, et al.

Nutr Cancer. 2000; 37(1):108-16.

Four selenocysteine-containing proteins (gastrointestinal glutathione peroxidase, plasma glutathione peroxidase, selenoprotein P, and thioredoxin reductase-alpha) are expressed in the colonic mucosa. Because of their antioxidant functions, a protective role in colon carcinogenesis is discussed. The aim of this study was to elucidate an involvement of gastrointestinal selenoproteins during the adenoma-carcinoma sequence. Matched pairs of biopsies of colorectal adenomas and adjacent normal mucosa from 11 patients were analyzed for mRNA expression, protein expression, or enzyme activity of selenoproteins by Northern blot, Western blot, or enzymatic tests. All adenomas revealed a marked reduction of selenoprotein P and a variable increase of gastrointestinal glutathione peroxidase mRNA compared with adjacent tissue. Thioredoxin reductase-alpha and plasma glutathione peroxidase mRNA expression were not altered in adenomas. The Northern blot results were confirmed by Western blot analysis or enzyme activity measurement, respectively. We conclude that gastrointestinal glutathione peroxidase and selenoprotein P play a complementary role in the antioxidative cell defense along the adenoma-carcinoma sequence. It remains to be shown whether upregulation of gastrointestinal glutathione peroxidase in adenomas represents a compensatory mechanism to reduce susceptibility for oxidative damage resulting from the loss of selenoprotein P

Cimetidine and colorectal cancer--old drug, new use?

Morris DL, Adams WJ.

Nat Med. 1995 Dec; 1(12):1243-4.

Bioactivity of well-defined green tea extracts in multicellular tumor spheroids.

Mueller-Klieser W, Schreiber-Klais S, Walenta S, et al.

Int J Oncol. 2002 Dec; 21(6):1307-15.

The effect of green tea extracts (GTE) of a reproducible, well-defined composition on cellular viability, proliferation, and antioxidant defense was investigated in multicellular spheroids derived from WiDr human colon adenocarcinoma cells. The maximum GTE concentration investigated, i.e. 100 micro g GTE/ml, was equivalent to the plasma concentration commonly measured in humans drinking 6-10 cups of green tea per day. This GTE concentration lead to a substantial retardation of spheroid volume growth with diameters reaching only half the size of untreated aggregates. Flow cytometric analysis and immunocytochemistry showed an enhanced accumulation of cells in G2/M and in the non-proliferating compartment, respectively. The emergence of central necrosis occurred at larger spheroid diameters compared to control conditions leading to a significant increase (p<0.05) in the thickness of the viable cell rim (mean +/- SD) from 240+/-49.9 micro m to 294+/-69.5 micro m. This was associated with an elevation of the intracellular GSH concentration and, thus, of cellular antioxidant defense, as shown by HPLC analysis. A considerable toxicity, however, was found at these GTE levels in single cells. Cells did not adhere to culture dishes nor did they aggregate to form spheroids when plated as a suspension with GTE already in the culture medium. The findings show that green tea constituents interfere with early phases of tumorigenesis at a cellular level, e.g., by reducing cell-substratum and cell-cell interaction, enhancing G2/M arrest, and retarding spheroid volume growth. The differences in GTE effects between single cells and cell spheroids underline the importance of inclusion of spheroids in pharmaco-/toxicological testing

Effect of selenomethionine on N-methylnitronitrosoguanidine-induced colonic aberrant crypt foci in rats.

Mukherjee B, Basu M, Chatterjee M.

Eur J Cancer Prev. 2001 Aug; 10(4):347-55.

An association between low selenium intake and the incidence or prevalence of cancers is well known. Selenium in the form of selenomethionine supplemented in drinking water has been found to be highly effective in reducing tumour incidence and preneoplastic foci during the development of hepatocarcinogenesis in rats in our previous studies. Here, an attempt has been made to investigate whether the dose and form of selenium found to be effective during hepatocarcinogenesis is equally effective in N-methylnitronitrosoguanidine-induced colorectal carcinogenesis in terms of antioxidant defence enzyme systems, DNA chain breaks and incidences of aberrant crypt foci. Treatment with selenomethionine either on initiation or on selection/promotion, or during the entire experiment showed that selenomethionine was most effective in regulating the cellular antioxidant defence systems, DNA chain break control and reducing aberrant crypt foci in the colorectal tissues of rats. Our results also confirm that selenium is particularly effective in limiting the action of the carcinogen during the initiation phase of this colorectal carcinogenesis, just as we found with hepatocarcinogenesis in our previous studies

Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease.

Munkholm P.

Aliment Pharmacol Ther. 2003 Sep; 18 Suppl 2:1-5.

Although colorectal cancer (CRC), complicating ulcerative colitis and Crohn's disease, only accounts for 1-2% of all cases of CRC in the general population, it is considered a serious complication of the disease and accounts for approximately 15% of all deaths in inflammatory bowel disease (IBD) patients. The magnitude of the risk was found to differ, even in population-based studies. Recent figures suggest that the risk of colon cancer for people with IBD increases by 0.5-1.0% yearly, 8-10 years after diagnosis. The magnitude of CRC risk increases with early age at IBD diagnosis, longer duration of symptoms, and extent of the disease, with pancolitis having a more severe inflammation burden and risk of the dysplasia-carcinoma cascade. Considering the chronic nature of the disease, it is remarkable that there is such a low incidence of CRC in some of the population-based studies, and possible explanations have to be investigated. One possible cancer-protective factor could be treatment with 5-aminosalicylic acid preparations (5-ASAs). Adenocarcinoma of the small bowel is extremely rare, compared with adenocarcinoma of the large bowel. Although only few small bowel cancers have been reported in Crohn's disease, the number was significantly increased in relation to the expected number

Beef induces and rye bran prevents the formation of intestinal polyps in Apc(Min) mice: relation to beta-catenin and PKC isozymes.

Mutanen M, Pajari AM, Oikarinen SI.

Carcinogenesis. 2000 Jun; 21(6):1167-73.

Epidemiological studies suggest that high consumption of red meat and saturated fat and low consumption of fiber are associated with an increased risk of colon cancer. Therefore, we studied whether diets high in red meat or high in different grain fibers as well as inulin, polydisperse beta(2-->1) fructan, could affect the formation of intestinal polyps in Apc(Min) mice. Min mice were fed the following high-fat (40% of energy) diets for 5-6 weeks; a high-beef diet and a casein-based diet without added fiber or casein-based diet with 10% (w/w) oat, rye or wheat bran, or 2.5% (w/w) inulin. One group had a normal low-fat AIN93-G diet. The mice fed the rye-bran diet had the lowest number of polyps in the distal small intestine [15.4 +/- 8.7 (mean +/- SD)], and in the entire intestine (26.4 +/- 12.1). The rye-bran group differed significantly (P = 0. 001-0.004) from the beef group (36.6 +/- 9.4 and 52.8 +/- 13.2). In addition, the beef group differed significantly from the AIN93-G group (P = 0.009) and also from the wheat-bran group (21.0 +/- 6.1 and 35.0 +/- 8.2; P = 0.02) in the distal small intestine. The inulin group (32.9 +/- 14.3 and 49.3 +/- 16.3), on the other hand, was close to the beef group and it differed significantly from the rye-bran group in the distal small intestine. The number of animals bearing tumors in the colon + caecum was only 33% in the rye-bran group when compared with 89% in the beef and 100% in the inulin groups. The mice fed the rye-bran and beef diets had the lowest levels of cytosolic beta-catenin (0.60 +/- 0.42 and 0.67 +/- 0.26) and they differed significantly (P = 0.040 and 0.062) from the mice fed the oat-bran diet (1.46 +/- 0.43). No differences between groups in expression of protein kinase C (PKC) alpha, betaII, delta and zeta were found. The four PKC isozymes were positively correlated with cytosolic beta-catenin levels (r = 0.62-0.68; P < 0.0001)

Telomerase inhibition, telomere shortening, and senescence of cancer cells by tea catechins.

Naasani I, Seimiya H, Tsuruo T.

Biochem Biophys Res Commun. 1998 Aug 19; 249(2):391-6.

Animal in vivo studies and human epidemiological observations indicated potent anticancer effects for tea. Here we demonstrate that epigallocatechin gallate (EGCG), a major tea catechin, strongly and directly inhibits telomerase, an enzyme essential for unlocking the proliferative capacity of cancer cells by maintaining the tips of their chromosomes. Telomerase inhibition was elaborated in a cell-free system (cell extract) as well as in living cells. In addition, the continued growth of two representative human cancer cell lines, U937 monoblastoid leukemia cells and HT29 colon adenocarcinoma cells, in the presence of nontoxic concentrations of EGCG showed life span limitations accompanied with telomere shortening, chromosomal abnormalities, and expression of the senescence-associated beta-galactosidase. It is suggested that telomerase inhibition could be one of the major mechanisms underlying the anticancer effects of tea

Cigarette smoking, alcohol use, and colorectal adenoma in Japanese men and women.

Nagata C, Shimizu H, Kametani M, et al.

Dis Colon Rectum. 1999 Mar; 42(3):337-42.

PURPOSE: The aim of this study was to examine the relationships between smoking and alcohol use and risk of colorectal adenoma. METHODS: Information about smoking, alcohol use, and other lifestyle variables were obtained prospectively from 14,427 male and 17,125 female residents in a city of Gifu Prefecture, Japan, by a self-administered questionnaire in September, 1992. Colorectal adenomas were newly diagnosed in 181 men and 78 women in this cohort between January, 1993 and December, 1995 by colonoscopic examination at two major hospitals of the city. Gender-specific and site-specific relative risks and 95 percent confidence intervals adjusted for age and for age plus other potential confounding factors were calculated by using logistic regression models. RESULTS: Thirty or more years of smoking was significantly associated with risk of adenoma in general compared with never having smoked in both men and women (relative risk, 1.60; 95 percent confidence interval, 1.02-2.62 and relative risk, 4.54; 95 percent confidence interval, 2.04-9.08, respectively). Effect of smoking was stronger in the proximal colon. After adjusting for age and carbohydrate intake, total alcohol intake was not associated with risk of adenoma in any site in the colon in men. Sake drinkers were at significantly increased risk of adenoma in general, but the dose-response relationship was not statistically significant. Risk of adenoma in the rectum was not significantly increased for those who consumed >30.3 g/day of ethanol (relative risk, 5.7). CONCLUSION: These data suggest that smoking is a risk factor of adenoma in Japanese men and women. The role of alcohol, however, is less clear

Folic acid mediated attenuation of loss of heterozygosity of DCC tumor suppressor gene in the colonic mucosa of patients with colorectal adenomas.

Nagothu KK, Jaszewski R, Moragoda L, et al.

Cancer Detect Prev. 2003; 27(4):297-304.

Loss of heterozygosity (LOH) and/or inactivation of tumor suppressor genes are implicated in the initiation and progression of many malignancies, including colorectal cancer. Although accumulating evidence suggests a chemopreventive role for folate in colorectal cancer, regulatory mechanisms are poorly understood. The primary objective of the current investigation was to determine whether folic acid would prevent LOH of the three tumor suppressor genes, deleted in colorectal cancer (DCC), adenomatous polyposis coli (APC) and p53 in macroscopically normal appearing rectal mucosa of patients with adenomatous polyps. In addition, the effect of folic acid on rectal mucosal proliferation was determined. Twenty patients were randomized in a double-blind study to receive either folic acid 5mg once daily or identical placebo tablets for 1 year. Genomic DNA and total protein were extracted from the rectal mucosa at baseline and after 1 year of treatment and analyzed for LOH and protein levels of APC, DCC and p53 genes. In addition, paraffin-embedded mucosal specimens were analyzed for proliferating cell nuclear antigen (PCNA) immunoreactivity, as a measure of cellular proliferative activity. Folate supplementation prevented LOH of DCC gene in five out of five (100%) patients who demonstrated baseline heterozygosity, whereas two out of four (50%) placebo-treated patients with baseline heterozygosity demonstrated allelic loss. Mucosal protein levels of DCC were also reduced in 7 of 10 (70%) placebo-treated patients compared to only 2 of 10 (20%) of patients treated with folate. Levels increased, however, in eight and three patients in the folic acid and placebo groups, respectively (P<0.02). Folic acid caused no change in allelic status of either APC or p53 gene. Folate supplementation caused a small, but not statistically significant, 16% reduction in mucosal proliferation, whereas placebo treatment resulted in a 88% (P<0.05) increase in this parameter, when compared with the corresponding baseline values. Our results indicate that folic acid prevents an increase in proliferation and arrests LOH of DCC gene and also stabilizes its protein in normal appearing rectal mucosa of patients with colorectal adenomas. Taken together, our data suggest that one of the ways folate may exert its chemopreventive effect is by stabilizing certain tumor suppressor gene(s) and preventing further increases in proliferation

Preoperative serum level of CA19-9 predicts recurrence after curative surgery in node-negative colorectal cancer patients.

Nakagoe T, Sawai T, Tsuji T, et al.

Hepatogastroenterology. 2003 May; 50(51):696-9.

BACKGROUND/AIMS: We hypothesize that a subset of node-negative colorectal cancer patients exists that is at high risk for recurrence after curative surgery. Preoperative serum levels of sialyl Lewisa (CA19-9), sialyl Lewisx (SLX), sialyl Tn (STN), and carcinoembryonic (CEA) antigens were analyzed for their value in predicting for such a group. METHODOLOGY: One-hundred-forty-five patients with node-negative, T1-4, M0 colorectal cancers were divided into groups of low or high serum antigen levels. Disease-free interval served as the endpoint in evaluating the prognostic strength of each variable. RESULTS: Twenty-seven patients (18.6%) were included in the high group for CA19-9 antigen, 11 (7.6%) for SLX, 13 (9.0%) for STN, and 51 (35.2%) for CEA. The median follow-up was 62.1 months. As compared to those with low levels, patients with elevated CA19-9 had a shorter disease-free interval (P = 0.0026). No significant difference in disease-free interval was noted between low and high groups of SLX, STN, and CEA antigens. Cox regression analysis identified elevated serum CA19-9 level as a predictor for decreased disease-free interval, independent of T-stage or tumor location. CONCLUSIONS: Elevated preoperative serum levels of CA19-9 may serve as a useful marker in identifying patients with node-negative colorectal cancers at high risk for recurrence after surgery

Suppression of intestinal polyp development by nimesulide, a selective cyclooxygenase-2 inhibitor, in Min mice.

Nakatsugi S, Fukutake M, Takahashi M, et al.

Jpn J Cancer Res. 1997 Dec; 88(12):1117-20.

Nonsteroidal anti-inflammatory drugs (NSAIDs) suppress colon carcinogenesis in man and experimental animals. However, conventional NSAIDs inhibit both cyclooxygenase (COX) isoforms, COX-1 and COX-2, and cause gastrointestinal side-effects. Nimesulide, a selective inhibitor of COX-2, is much less ulcerogenic. We, therefore, examined its influence on the development of intestinal polyps in Min mice. Female Min mice at 4 weeks old were given 400 ppm nimesulide in their diet for 11 weeks. This treatment resulted in a significant reduction of the numbers of both small and large intestinal polyps, the total being 52% of that in untreated control Min mice. The size of the polyps in the nimesulide-treated group was also significantly decreased. The results suggest that nimesulide is a good candidate as a chemopreventive agent for human colon cancer with low toxicity

Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin.

Nangia-Makker P, Hogan V, Honjo Y, et al.

J Natl Cancer Inst. 2002 Dec 18; 94(24):1854-62.

BACKGROUND: The role of dietary components in cancer progression and metastasis is an emerging field of clinical importance. Many stages of cancer progression involve carbohydrate-mediated recognition processes. We therefore studied the effects of high pH- and temperature-modified citrus pectin (MCP), a nondigestible, water-soluble polysaccharide fiber derived from citrus fruit that specifically inhibits the carbohydrate-binding protein galectin-3, on tumor growth and metastasis in vivo and on galectin-3-mediated functions in vitro. METHODS: In vivo tumor growth, angiogenesis, and metastasis were studied in athymic mice that had been fed with MCP in their drinking water and then injected orthotopically with human breast carcinoma cells (MDA-MB-435) into the mammary fat pad region or with human colon carcinoma cells (LSLiM6) into the cecum. Galectin-3-mediated functions during tumor angiogenesis in vitro were studied by assessing the effect of MCP on capillary tube formation by human umbilical vein endothelial cells (HUVECs) in Matrigel. The effects of MCP on galectin-3-induced HUVEC chemotaxis and on HUVEC binding to MDA-MB-435 cells in vitro were studied using Boyden chamber and labeling assays, respectively. The data were analyzed by two-sided Student's t test or Fisher's protected least-significant-difference test. RESULTS: Tumor growth, angiogenesis, and spontaneous metastasis in vivo were statistically significantly reduced in mice fed MCP. In vitro, MCP inhibited HUVEC morphogenesis (capillary tube formation) in a dose-dependent manner. In vitro, MCP inhibited the binding of galectin-3 to HUVECs: At concentrations of 0.1% and 0.25%, MCP inhibited the binding of galectin-3 (10 micro g/mL) to HUVECs by 72.1% (P =.038) and 95.8% (P =.025), respectively, and at a concentration of 0.25% it inhibited the binding of galectin-3 (1 micro g/mL) to HUVECs by 100% (P =.032). MCP blocked chemotaxis of HUVECs toward galectin-3 in a dose-dependent manner, reducing it by 68% at 0.005% (P<.001) and inhibiting it completely at 0.1% (P<.001). Finally, MCP also inhibited adhesion of MDA-MB-435 cells, which express galectin-3, to HUVECs in a dose-dependent manner. CONCLUSIONS: MCP, given orally, inhibits carbohydrate-mediated tumor growth, angiogenesis, and metastasis in vivo, presumably via its effects on galectin-3 function. These data stress the importance of dietary carbohydrate compounds as agents for the prevention and/or treatment of cancer

A very low dose of green tea polyphenols in drinking water prevents N-methyl-N-nitrosourea-induced colon carcinogenesis in F344 rats.

Narisawa T, Fukaura Y.

Jpn J Cancer Res. 1993 Oct; 84(10):1007-9.

The effect of tea polyphenols, major constituents of tea, on colon carcinogenesis was investigated. A total of 129 female F344 rats were given an intrarectal instillation of 2 mg of N-methyl-N-nitrosourea 3 times a week for 2 weeks, and received a water solution of green tea extract (GTE) as drinking water throughout the experiment. Autopsies at week 35 revealed significantly lower incidence of colon carcinomas in rats ingesting 0.05%, 0.01% or 0.002% GTE solution than in controls ingesting 0% GTE solution: 43%, 40% and 33% vs. 67%. The data suggest that GTE, even at a very low dose (0.002% solution), has a potent inhibitory effect on colon carcinogenesis

Cholecystectomy as a risk factor for colorectal adenomatous polyps and carcinoma.

Neugut AI, Murray TI, Garbowski GC, et al.

Cancer. 1991 Oct 1; 68(7):1644-7.

Multiple studies have suggested a possible relationship between prior cholecystectomy and the occurrence of subsequent colorectal carcinoma. This relationship has been particularly noticed among female patients and for right-sided lesions of the colon. In the current study, the authors undertook a case-control study among patients who underwent colonoscopy in three private practices in New York City between April 1986 and March 1988. Over this period, 302 adenomatous polyp cases, 106 colon cancer cases, and 507 controls were interviewed regarding their prior history of cholecystectomy. Overall, no significant association was observed between cholecystectomy and either colorectal adenomatous polyps or cancer. Cholecystectomy does not appear to be a significant risk factor for colorectal neoplasia

Induction of cancer cell apoptosis by alpha-tocopheryl succinate: molecular pathways and structural requirements.

Neuzil J, Weber T, Schroder A, et al.

FASEB J. 2001 Feb; 15(2):403-15.

The vitamin E analog alpha-tocopheryl succinate (alpha-TOS) can induce apoptosis. We show that the proapoptotic activity of alpha-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented alpha-TOS-triggered apoptosis. More selective effectors indicated that alpha-TOS reduced PKCalpha isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCalpha inhibition in alpha-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCalpha overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of alpha-TOS-induced proapoptotic signals. Structural analogs revealed that alpha-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, alpha-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects

Vitamin E succinate and cancer treatment: a vitamin E prototype for selective antitumour activity.

Neuzil J.

Br J Cancer. 2003 Nov 17; 89(10):1822-6.

Great hope has been given to micronutrients as anticancer agents, since they present natural compounds with beneficial effects for normal cells and tissues. One of these is vitamin E (VE), an antioxidant and an essential component of biological membranes and circulating lipoproteins. In spite of a number of epidemiological and intervention studies, little or no correlation between VE intake and incidence of cancer has been found. Recent reports have identified a redox-silent analogue of VE, alpha-tocopheryl succinate (alpha-TOS), as a potent anticancer agent with a unique structure and pharmacokinetics in vivo. alpha-TOS is highly selective for malignant cells, inducing them into apoptotic death largely via the mitochondrial route. The molecule of alpha-TOS may be modified so that analogues with higher activity are generated. Finally, alpha-TOS and similar agents are metabolised to VE, thereby yielding a compound with a secondary beneficial activity. Thus, alpha-TOS epitomises a group of novel compounds that hold substantial promise as future anticancer drugs. The reasons for this optimistic notion are discussed in the following paragraphs

Roles of micronutrients in cancer prevention: recent evidence from the laboratory.

Newberne PM, Locniskar M.

Prog Clin Biol Res. 1990; 346:119-34.

In addition to differences in needs for dietary quality and quantity, humans, as individuals and as subsets of the population, are exposed to variations in climate, stress, environmental contaminants and other confounding factors which likely impinge on susceptibility to cancer. Despite the complexity of lifestyles and dietary habits, it is impressive to review available data on the relation of nutrients to cancer. There is sufficient parallelism between controlled animal studies and human behavior that we are compelled to believe that a variety of essential nutrients can modify carcinogenesis in humans and in lower animals. The micronutrients which appear to meet criteria for classifying them as protective agents in animal models include vitamin A and some of the synthetic retinoids; beta carotene; folic acid; vitamin C; choline/methionine; zinc, and selenium. Some of the others have suggestive effects but in the view of this author, the data are often equivocal, inadequate, or conflicting. These observations clearly support the proposal that animal studies have made enormous contributions in the past 15-20 years to our understanding of carcinogenesis and that this will continue into the future. From the data now available we can state with confidence that animal studies have shown that nutrients can modify the carcinogenesis process at specific sites and through a variety of mechanisms. These include effects on the formation of carcinogens from precursors; effects on metabolism of the carcinogen; effects on one or more stages of initiation, promotion, and progression; host defense mechanisms; cellular differentiation and on growth and metastasis of the tumor. The tools of the molecular biology, just now emerging in the field of nutrition, should have an immense impact on determining more accurately where nutrients exert their effects, how this is accomplished, and to suggest appropriate prevention and intervention techniques. Using molecular biology, combined with traditional and newer methods of toxicology and pathology, we should be able within a few years to better understand carcinogenesis and with such knowledge in hand to make sound recommendations about dietary habits to the public

Ranitidine improves certain cellular immune responses in asymptomatic HIV-infected individuals.

Nielson HJ, Svenningsen A, Moesgaard F, et al.

J Acquir Immune Defic Syndr. 1991; 4(6):577-84.

Human immunodeficiency virus (HIV) infection is characterized by a progressive impairment in immunocompetence leading to severe opportunistic infections and malignancies. In a double-blind, placebo-controlled study, the potential impact of immunomodulation by oral ranitidine, 600 mg daily, for 28 days was studied in 18 HIV-positive patients (CDC group II). All were without clinical signs of infections and were not treated with other known immunomodulating agents. Several immunological parameters related to HIV infection were studied and confirmed to be impaired early in HIV infection. Spontaneous and in vitro interleukin-2- and interferon-alpha-stimulated natural killer cell activity improved in the ranitidine-treated patients in contrast to a decrease in nontreated patients (#p less than 0.03, #p less than 0.01, #p less than 0.02 between groups, respectively). Furthermore, T-cell blastogenesis to phytohemagglutinin stimulation and soluble interleukin-2 receptors in serum increased in ranitidine-treated patients compared with nontreated patients (#p less than 0.01). However, ranitidine treatment did not change CD4+ cell counts. Although the significant improvement in immunocompetence shown in this study is small, the present result indicates the need for further trials with immunomodulation by ranitidine in HIV-infected individuals

Evidence of a dual role of endogenous histamine in angiogenesis.

Norrby K.

Int J Exp Pathol. 1995 Apr; 76(2):87-92.

The specific activation of mast cells in situ causes vigorous local mast-cell mediated angiogenesis (MCMA). The mast cell is a major source of histamine and, as recently reported, specific histamine H1- and H2-membrane receptor antagonists are able individually to significantly suppress MCMA in rats, as assessed using the mesenteric window angiogenesis assay (MWAA). In addition to membrane receptors for histamine, a type of intracellular histamine receptors, designated Hic, has been described. It is now demonstrated that the potent Hic-receptor antagonist DPPE (N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl), administered parenterally, stimulates MCMA significantly in rats, as quantified by the MWAA. Although the target cell(s) are not known, there are several ways by which their Hic receptors could be activated: uptake of histamine released from mast cells, mobilization from preformed cytoplasmic and nuclear stores, and production of de novo histamine by histidine decarboxylase activity. The fact that the occupancy by histamine of H1- and H2-membrane receptors stimulates MCMA and the occupancy by histamine of Hic inhibits MCMA suggests that endogenous histamine is capable of regulating angiogenesis by a dual mode of action. This is apparently the first report ascribing a dual role of this type in angiogenesis to a single molecule

The National Polyp Study. Patient and polyp characteristics associated with high-grade dysplasia in colorectal adenomas.

O'Brien MJ, Winawer SJ, Zauber AG, et al.

Gastroenterology. 1990 Feb; 98(2):371-9.

The National Polyp Study (NPS), a randomized clinical trial to evaluate effective surveillance of patients discovered to have one or more colorectal adenomas, was the framework for this statistical analysis which used a multiple logistic model to assess the independent risk factors of patient and polyp characteristics associated with high-grade dysplasia in adenomas. The database included 3371 adenomas from 1867 patients. Adenoma size and the extent of the villous component were found to be the major independent polyp risk factors associated with high-grade dysplasia (p less than 0.0001). The adjusted odds ratios were 3.3 for medium-sized adenomas and 7.7 for large adenomas relative to small adenomas and 2.7 for villous A adenomas, 3.4 for villous B adenomas, and 8.1 for villous C and D adenomas relative to tubular adenomas. Increased frequency of high-grade dysplasia in adenomas located distal to the splenic flexure was attributable mainly to increased size and villous component rather than to location per se. The adjusted odds ratio was 1.4 (p less than 0.11) for left-sided location. Multiplicity of adenomas affected the risk for high-grade dysplasia in patients but was dependent on adenoma size and villous component and was not an independent factor. The adjusted odds ratio was 1.3 (p less than 0.17) for multiplicity. Increasing age was associated with risk for high-grade dysplasia in patients, and this effect was independent of the effect of adenoma size and histological type. The adjusted odds ratio was 1.8 (p less than 0.0016) for age greater than or equal to 60 yr. Gender was not associated with high-grade dysplasia. The adjusted odds ratio was 1.0 (p less than 0.95) for men. The size of the patient series, the prospective nature of the data collection, the completeness of information on all patients, the requirements of complete examination of the entire colon and pathological examination of all lesions encountered, and the exclusion of patients with previously diagnosed adenomas are, collectively, features unique to this study. The detailed model provided by the analysis integrates multiple patient and adenoma factors associated with high-grade dysplasia in colorectal adenomas

Novel chemotherapeutic and targeted agents in metastatic colorectal cancer: the time has arrived.

O'Neil BH, Goldberg RM.

Expert Opin Investig Drugs. 2003 Dec; 12(12):1939-49.

Colorectal cancer is a common disease with a high rate of mortality and very well-understood genetics. Primary therapy still consists of relatively non-specific treatments: surgery, radiotherapy and chemotherapy. In this article, recent data in the now fast-moving field of treatment of unresectable metastatic colorectal cancer are reviewed, beginning with new developments in conventional cytotoxic therapies. A number of new cytotoxic agents appear to have at least some activity in this disease, including classes of drugs that have been effective to date. The very rapidly growing area of targeted therapy will also be expanded upon. This year, for the first time, there has been a targeted therapy shown convincingly to prolong survival for patients with unresectable metastatic colorectal cancer in a well-performed Phase III trial. This agent is bevacizumab, a humanised monoclonal antibody targeting the circulating proangiogenic growth factor vascular endothelial growth factor. Results with bevacizumab should lead to rapid expansion of the number of strategies targeting tumour neovasculature. Additionally, an antibody against the epidermal growth factor, cetuximab, has been shown to have both single-agent activity and the potential ability to partially reverse resistance to a chemotherapy drug. These advancements, as well as data on other novel treatment agents that have been studied specifically in patients with colorectal neoplasms, are discussed in detail

Relationship between age and site of colorectal cancer based on colonoscopy findings.

Okamoto M, Shiratori Y, Yamaji Y, et al.

Gastrointest Endosc. 2002 Apr; 55(4):548-51.

BACKGROUND: Colorectal cancer occurs more frequently in older people. Because the population of aged persons is increasing, a better understanding of the characteristics of colorectal cancer with respect to age would be useful. The purpose of this study was to determine whether there is any relationship between the site of colorectal adenoma and adenocarcinoma in the colon and age. METHODS: Colonoscopy was performed (September 1995 to December 1998) on 2942 consecutive patients (1907 men, 1035 women; mean age 61 years, range 11 to 95 years) with no history of colorectal adenoma, adenocarcinoma, or inflammatory bowel disease. The occurrence of colorectal neoplasia, histologically proven as adenoma or adenocarcinoma, was analyzed for a possible association between site in the colon and patient age. RESULTS: Adenocarcinoma was found in 191 patients (196 lesions). The proportion of patients with right-sided colonic adenocarcinoma increased with patient age: < 50 years, 15% (2/13); 50 to 59 years, 21% (8/39); 60 to 69 years, 32% (18/57); 70 to 79 years, 42% (25/49); > or =80 years, 57% (16/28). The proportion of patients with right-sided adenoma did not significantly differ among age groups: < 50 years, 40% (98/246); 50 to 59 years, 41% (280/678); 60 to 69 years, 46% (459/1001); 70 to 79 years, 53% (270/508); and > or =80 years, 57% (87/152). CONCLUSION: The frequency of right-sided colon cancer increases with patient age. Hence, colonoscopy may be indicated in the elderly for colorectal cancer screening. Over half of colon carcinomas may be missed if sigmoidoscopy alone is used for screening

Evaluation of K-RAS gene in colorectal cancer.

Okulczyk B, Piotrowski Z, Kovalchuk O, et al.

Folia Histochem Cytobiol. 2003; 41(2):97-100.

The aim of the study was to assess the prevalence of K-RAS gene mutations in colorectal cancer and their role in diagnosis and prognosis. The study involved 36 patients with colorectal cancer at different stages of the disease progression and with different histopathologic grading. Mutations of codon 12 of K-RAS gene investigated using PCR-RFLP technique were found in 15 patients (41.67%). Although no statistically significant correlation was observed between the disease progression, histopathologic findings, gender and age, we suppose that assessment of K-RAS gene mutations might be of clinical value in the prognosis of colorectal cancer

[Radiofrequency ablation therapy combined with intrahepatic arterial infusion chemotherapy for liver metastasis of colorectal cancer].

Otsuka S, Inagaki M, Miyoshi K, et al.

Gan To Kagaku Ryoho. 2003 Oct; 30(11):1598-601.

We performed radiofrequency ablation (RFA) therapy combined with intrahepatic arterial infusion chemotherapy for 7 patients with liver metastasis from colorectal cancer. Synchronous metastasis accounted for 5 cases and metachronous for 2 cases. Two cases were H1, 2 cases H2, and 3 cases H3. Following the resection of colorectal primary lesion, we performed RFA for liver metastasis, using a Cool-tip electrode purchased from Radionics (Burlington, MA, USA). The mean number of sessions per patient was 5.1 (1-10). Ablation time of each session was changed according to tumor size, as follows: less than 1 cm in diameter: 2 min, 2 cm: 5 min, 2.5 cm: 10 min. By using intra-operative catheterization, weekly intrahepatic arterial infusion chemotherapy was performed for liver metastasis. Excellent ablation was achieved in all cases by CT evaluation and no significant side-effect was observed. Average observation period was 15 months (maximal survival period was 31 months) and 6 patients are alive. RFA therapy combined with intrahepatic arterial infusion chemotherapy achieved excellent therapeutic effect, and maintained good quality of life in patients

Prediagnostic levels of carcinoembryonic antigen and CA 242 in colorectal cancer: a matched case-control study.

Palmqvist R, Engaras B, Lindmark G, et al.

Dis Colon Rectum. 2003 Nov; 46(11):1538-44.

PURPOSE: Carcinoembryonic antigen is the classical tumor marker for colorectal cancer. The main clinical utility is in monitoring patients with colorectal cancer. Like carcinoembryonic antigen, the plasma level of CA 242 is elevated in patients with colorectal cancer. The purpose of this study was to investigate whether the plasma levels of carcinoembryonic antigen and/or CA 242 were elevated before clinical diagnosis of colorectal cancer. METHODS: The Northern Sweden Health and Disease Cohort was linked to the Swedish National and Regional Cancer registries, and 124 prospective cases with colorectal cancer were identified. Two referents for each case were randomly selected and matched for gender, age, date of sampling, and fasting time. Plasma from the included patients was analyzed for carcinoembryonic antigen and CA 242 using specific immunoassays. RESULTS: An elevated level of carcinoembryonic antigen before diagnosis was associated with an increased risk of developing manifest colorectal cancer (adjusted odds ratio, 7.9; 95 percent confidence interval, 2.1-29.1; P = 0.002). An elevated level of CA 242 was not significantly related to colorectal cancer risk. Elevated carcinoembryonic antigen levels were only seen in samples collected in the two-year time interval immediately before diagnosis. In this group, 30.4 percent of all plasma samples from cases were carcinoembryonic antigen-positive and 71.4 percent were future Dukes A or B cases. The specificity of the carcinoembryonic antigen test for identifying future colorectal cancer patients was 0.99 with a sensitivity of 0.12. For CA 242 the specificity was 0.92 and the sensitivity was 0.1. CONCLUSIONS: Elevated carcinoembryonic antigen levels strongly indicate occult colorectal cancer. Although the specificity of the carcinoembryonic antigen test in its present form is high, the sensitivity is disappointingly low, prohibiting the use of the carcinoembryonic antigen test for mass screening

Combined resection and radiofrequency ablation for advanced hepatic malignancies: results in 172 patients.

Pawlik TM, Izzo F, Cohen DS, et al.

Ann Surg Oncol. 2003 Nov; 10(9):1059-69.

BACKGROUND: Resection combined with radiofrequency ablation (RFA) is a novel approach in patients who are otherwise unresectable. The objective of this study was to investigate the safety and efficacy of hepatic resection combined with RFA. METHODS: Patients with multifocal hepatic malignancies were treated with surgical resection combined with RFA. All patients were followed prospectively to assess complications, treatment response, and recurrence. RESULTS: Seven hundred thirty seven tumors in 172 patients were treated (124 with colorectal metastases; 48 with noncolorectal metastases). RFA was used to treat 350 tumors. Combined modality treatment was well tolerated with low operative times and minimal blood loss. The postoperative complication rate was 19.8% with a mortality rate of 2.3%. At a median follow-up of 21.3 months, tumors had recurred in 98 patients (56.9%). Failure at the RFA site was uncommon (2.3%). A combined total number of tumors treated with resection and RFA >10 was associated with a faster time to recurrence (P =.02). The median actuarial survival time was 45.5 months. Patients with noncolorectal metastases and those with less operative blood loss had an improved survival (P =.03 and P =.04, respectively), whereas radiofrequency ablating a lesion >3 cm adversely impacted survival (HR = 1.85, P =.04). CONCLUSIONS: Resection combined with RFA provides a surgical option to a group of patients with liver metastases who traditionally are unresectable, and may increase long-term survival

Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients.

Peet M, Murphy B, Shay J, et al.

Biol Psychiatry. 1998 Mar 1; 43(5):315-9.

BACKGROUND: It has been hypothesized that depletion of cell membrane n3 polyunsaturated fatty acids (PUFA), particularly docosahexanoic acid (DHA), may be of etiological importance in depression. METHODS: We measured the fatty acid composition of phospholipid in cell membranes from red blood cells (RBC) of 15 depressive patients and 15 healthy control subjects. RESULTS: Depressive patients showed significant depletions of total n3 PUFA and particularly DHA. Incubation of RBC from control subjects with hydrogen peroxide abolished all significant differences between patients and controls. CONCLUSIONS: These findings suggest that RBC membranes in depressive patients show evidence of oxidative damage. Possible interpretations, and implications for the etiology and treatment of depression, are discussed

Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer.

Peltomaki P, Vasen HF.

Gastroenterology. 1997 Oct; 113(4):1146-58.

BACKGROUND & AIMS: Germline mutations in four DNA mismatch repair genes are known to cause susceptibility to hereditary nonpolyposis colorectal cancer (HNPCC). The rapidly increasing information about these mutations needs to be collected and appropriately stored to facilitate further studies on the biological and clinical significance of the findings. METHODS: The International Collaborative Group on HNPCC has established a database of DNA mismatch repair gene mutations and polymorphisms. In this report, 126 predisposing mutations were analyzed. RESULTS: A majority of the mutations affected either the Mut L homologue (MLH) 1 (n = 75) or the Mut S homologue (MSH) 2 (n = 48) and were quite evenly distributed, with some clustering in MSH2 exon 12 and MLH1 exon 16. Most MSH2 mutations consisted of frameshift (60%) or nonsense changes (23%), whereas MLH1 was mainly affected by frameshift (40%) or missense alterations (31%). Although most mutations were unique, a few common recurring mutations were identified. Of the families studied (n = 202), 82% met the Amsterdam criteria and 15% did not; the general mutation profile was similar in both groups. CONCLUSIONS: The construction of mutation profiles will facilitate the development of diagnostic strategies in HNPCC

Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse, a model of familial adenomatous polyposis.

Perkins S, Verschoyle RD, Hill K, et al.

Cancer Epidemiol Biomarkers Prev. 2002 Jun; 11(6):535-40.

Curcumin, the major yellow pigment in turmeric, prevents the development of adenomas in the intestinal tract of the C57Bl/6J Min/+ mouse, a model of human familial APC. To aid the rational development of curcumin as a colorectal cancer-preventive agent, we explored the link between its chemopreventive potency in the Min/+ mouse and levels of drug and metabolites in target tissue and plasma. Mice received dietary curcumin for 15 weeks, after which adenomas were enumerated. Levels of curcumin and metabolites were determined by high-performance liquid chromatography in plasma, tissues, and feces of mice after either long-term ingestion of dietary curcumin or a single dose of [(14)C]curcumin (100 mg/kg) via the i.p. route. Whereas curcumin at 0.1% in the diet was without effect, at 0.2 and 0.5%, it reduced adenoma multiplicity by 39 and 40%, respectively, compared with untreated mice. Hematocrit values in untreated Min/+ mice were drastically reduced compared with those in wild-type C57Bl/6J mice. Dietary curcumin partially restored the suppressed hematocrit. Traces of curcumin were detected in the plasma. Its concentration in the small intestinal mucosa, between 39 and 240 nmol/g of tissue, reflects differences in dietary concentration. [(14)C]Curcumin disappeared rapidly from tissues and plasma within 2-8 h after dosing. Curcumin may be useful in the chemoprevention of human intestinal malignancies related to Apc mutations. The comparison of dose, resulting curcumin levels in the intestinal tract, and chemopreventive potency suggests tentatively that a daily dose of 1.6 g of curcumin is required for efficacy in humans. A clear advantage of curcumin over nonsteroidal anti-inflammatory drugs is its ability to decrease intestinal bleeding linked to adenoma maturation

Meat and cancer: haemoglobin and haemin in a low-calcium diet promote colorectal carcinogenesis at the aberrant crypt stage in rats Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin Meat intake, metabolic genes and colorectal cancer Red meat intake, CYP2E1 genetic polymorphisms, and colorectal cancer risk Meat consumption, cigarette smoking, and genetic susceptibility in the etiology of colorectal cancer: results from a Dutch prospective study Diet and colorectal cancer: an investigation of the lectin/galactose hypothesis B-vitamin intake, metabolic genes, and colorectal cancer risk (United States) Macronutrients and colorectal cancer: a Swiss case-control study 191.

Pierre F, Tache S, Petit CR, et al.

Carcinogenesis. 2003; 24(10):1683-90.

High intake of red meat, but not of white meat, is associated with an increased risk of colon cancer. However, red meat does not promote cancer in rodents. Haemin, added to low-calcium diets, increases colonic proliferation, and haemoglobin, added to high-fat diets, increases the colon tumour incidence in rats, an effect possibly due to peroxyl radicals. We thus speculated that haem might be the promoting agent in meat, and that prevention strategies could use calcium and antioxidants. These hypotheses were tested in rats at the aberrant crypt foci (ACF) stage at 100 days. F344 rats (n = 124) were given an injection of azoxymethane and were then randomized to 11 groups fed with low-calcium (20 micro mol/g) AIN76-based diets, containing 5% safflower oil. Haemin (0.25, 0.5 and 1.5 micro mol/g) or haemoglobin (1.5 and 3 micro mol haem/g) was added to five experimental diets, compared with a control diet without haem. Three other high-haemin diets (1.5 micro mol/g) were supplemented with calcium (250 micro mol/g), antioxidant butylated hydroxyanisole and rutin (0.05% each), and olive oil, which replaced safflower oil. Faecal water was assayed for lipid peroxidation by thiobarbituric acid reactive substances (TBARs) test, and for cytolytic activity. Haemin strikingly increased the ACF size, dose-dependently, from 2.6 to 11.4 crypts/ACF (all P < 0.001). The high-haemin diet also increased the number of ACF per colon (P < 0.001). Promotion was associated with increased faecal water TBARs and cytotoxicity. Calcium, olive oil and antioxidants each inhibited the haemin-induced ACF promotion, and normalized the faecal TBARs and cytotoxicity. The haemoglobin diets increased the number of ACF and faecal TBARs, but not the ACF size or the faecal cytotoxicity. In conclusion, dietary haemin is the most potent known ACF promoter. Haemoglobin is also a potent promoter of colorectal carcinogenesis. The results suggest that myoglobin in red meat could promote colon cancer. Diets high in calcium, or in oxidation-resistant fats, may prevent the possible cancer-promoting effect of red meat. BACKGROUND: The role of dietary components in cancer progression and metastasis is an emerging field of clinical importance. Many stages of cancer progression involve carbohydrate-mediated recognition processes. We therefore studied the effects of high pH- and temperature-modified citrus pectin (MCP), a nondigestible, water-soluble polysaccharide fiber derived from citrus fruit that specifically inhibits the carbohydrate-binding protein galectin-3, on tumor growth and metastasis in vivo and on galectin-3-mediated functions in vitro. METHODS: In vivo tumor growth, angiogenesis, and metastasis were studied in athymic mice that had been fed with MCP in their drinking water and then injected orthotopically with human breast carcinoma cells (MDA-MB-435) into the mammary fat pad region or with human colon carcinoma cells (LSLiM6) into the cecum. Galectin-3-mediated functions during tumor angiogenesis in vitro were studied by assessing the effect of MCP on capillary tube formation by human umbilical vein endothelial cells (HUVECs) in Matrigel. The effects of MCP on galectin-3-induced HUVEC chemotaxis and on HUVEC binding to MDA-MB-435 cells in vitro were studied using Boyden chamber and labeling assays, respectively. The data were analyzed by two-sided Student's t test or Fisher's protected least-significant-difference test. RESULTS: Tumor growth, angiogenesis, and spontaneous metastasis in vivo were statistically significantly reduced in mice fed MCP. In vitro, MCP inhibited HUVEC morphogenesis (capillary tube formation) in a dose-dependent manner. In vitro, MCP inhibited the binding of galectin-3 to HUVECs: At concentrations of 0.1% and 0.25%, MCP inhibited the binding of galectin-3 (10 micro g/mL) to HUVECs by 72.1% (P =.038) and 95.8% (P =.025), respectively, and at a concentration of 0.25% it inhibited the binding of galectin-3 (1 micro g/mL) to HUVECs by 100% (P =.032). MCP blocked chemotaxis of HUVECs toward galectin-3 in a dose-dependent manner, reducing it by 68% at 0.005% (P<.001) and inhibiting it completely at 0.1% (P<.001). Finally, MCP also inhibited adhesion of MDA-MB-435 cells, which express galectin-3, to HUVECs in a dose-dependent manner. CONCLUSIONS: MCP, given orally, inhibits carbohydrate-mediated tumor growth, angiogenesis, and metastasis in vivo, presumably via its effects on galectin-3 function. These data stress the importance of dietary carbohydrate compounds as agents for the prevention and/or treatment of cancer. N-Nitroso compounds are suspected colorectal cancer (CRC) carcinogens to which individuals on a diet high in red meat (RM) may be particularly exposed. Many of these compounds undergo alpha-hydroxylation by CYP2E1 to form DNA adducts. The gene coding for this enzyme is polymorphic and thus may constitute a susceptibility factor for CRC. We conducted a population-based case-control study in Hawaii to test the association of two functional polymorphisms in CYP2E1 (the G1259C RsaI substitution and a 5' 96-bp insertion variant) with CRC, as well as their modifying effects on the association of RM and processed meat (PM) with this cancer. We obtained interviews and blood samples for 521 patients with CRC (165 with rectal cancer) and 639 controls of Japanese, Caucasian, or Hawaiian origin. Genotyping was performed by PCR. After adjustment for CRC risk factors, subjects with the 5' insert variant were found to be at a 60% increased risk (95% confidence interval, 1.1-2.5) for rectal cancer. Subjects who carry the insert and who were predicted to have been exposed to increased levels of nitrosamines, based on their high intake of RM or PM, were at a markedly greater increased risk (2- and 3-fold for RM and PM, respectively) for rectal cancer. No clear association was found for colon cancer. A similar increase in rectal cancer risk was found for CYP2E1 insert carriers who consumed salted/dried fish or Oriental pickled vegetables. These data provide additional support for the hypothesis that nitrosamines are carcinogenic to the rectum in humans and that RM and, in particular, PMs are significant sources of exposure for these compounds. OBJECTIVE: We evaluated the effect of meat consumption and cigarette smoking in combination with N-acetyltransferases 1 and 2 (NAT1 and NAT2), and glutathione S-transferase M1 (GSTM1) genotypes on colorectal cancer. METHODS: From a Dutch prospective study, after 8.5 years of follow-up, data of 102 incident colorectal cancer cases and a random sample of 537 controls frequency-matched for gender and age were analyzed. Baseline information on dietary and smoking habits, as well as blood samples for DNA isolation and genotyping, were available. RESULTS: Red meat intake increased colorectal cancer risk among men (OR 2.7; 95% CI 1.1-6.7 highest vs. lowest intake), whereas poultry and fish decreased risk among women (OR 0.5; 95% CI 0.2-1.07). Cigarette smoking for at least 16 years increased colorectal cancer risk among former smokers only (OR 2.7; 95% CI 1.0-7.4), compared to those having smoked for 15 years or less. NAT1 and NAT2 polymorphisms did not significantly modify these associations. High consumption of poultry and fish was inversely associated with colorectal cancer only in the presence of GSTM1. CONCLUSIONS: In this study meat consumption and former long-term smoking were associated with colorectal cancer. Associations of colorectal cancer with different types of meat were modified by gender and GSTM1 genotype. BACKGROUND & AIMS: Mucosal expression of terminal unsubstituted galactose is increased in colon cancer and precancer and allows interaction with mitogenic galactose-binding lectins of dietary or microbial origin. This study tests the hypothesis that galactose, which is variably plentiful in fruit and vegetable but not cereal fibers, might prevent cancer by binding and inhibiting such lectins. METHODS: Colorectal cancer cases (512) and controls (512) were matched for age, sex, primary care practitioner, and postal code. A 160-item food-frequency questionnaire was used to estimate their usual pre-illness (6 months previous) diet, aspirin intake, and exercise. RESULTS: Neither cereal fiber nor fruit and vegetable fiber were protective when assessed by univariate analysis, whereas dietary fiber galactose content showed a dose-related protective effect (odds ratio [OR] highest quartile/lowest quartile, 0.67; confidence interval [CI], 0.47-0.95) that remained protective when adjusted for energy, red meat, alcohol, calcium, protein and fat intake, regular aspirin usage, and exercise. Intake of nonlegume green vegetables, assessed because of the high lectin content of legumes, was also protective (OR, 0.54; CI, 0.35-0.81), but this was not independent of galactose. Protective effects of exercise and regular daily aspirin consumption and harmful effects of high energy consumption and high red meat intake were confirmed. CONCLUSIONS: The protective effect of fruit and vegetable fibers may be related to their galactose content. This provides further evidence that the association between diet and colon cancer is mediated via specific food components and may explain the discrepant results of studies addressing the protective effects of fiber. OBJECTIVE: This population-based case-control study was designed to investigate the interrelationships between polymorphisms in the methylenetetrahydrofolate (MTHFR C677T and A1298C) gene and other genes (MTR A2756G; MTRR A66G and CBS 844ins68), intake of B-vitamins and colorectal cancer risk (CRC). METHODS: We interviewed 727 CRC cases of Japanese, Caucasian, or Native Hawaiian origin and 727 controls matched on sex, age, and ethnicity. RESULTS: Compared to the homozygous wild-type genotype, the odds ratios for subjects with one or two MTHFR 677T variant alleles were 0.8 (0.6-1.1) and 0.7 (0.5-1.1), respectively (p for gene-dosage effect: 0.04). The TT genotype was associated with a 50-60% decrease in CRC risk among subjects with high intake of folate or vitamin B6, compared to those with the CC genotype and low levels of intake. The MTHFR 1298C and CBS8 44ins68 variant alleles were also found to be weakly protective against CRC and to act jointly with the 677T allele. CONCLUSIONS: This study provides additional evidence for a decreased CRC risk for subjects with the MTHFR 677T allele, particularly at high levels of folate and vitamin B6 intake. Our data also suggest that the relationships between CRC and the MTHFR A1298C and CBS 844ins68 polymorphisms warrant further study. BACKGROUND: A role of energy and various nutrients, including protein, sugar, saturated and unsaturated fats, in colorectal cancer risk has been suggested, but should be better defined. PATIENTS AND METHODS: The association between dietary intake of various macronutrients and colorectal cancer risk was analysed using data from a case-control study conducted between 1992 and 2000 in the Swiss Canton of Vaud. The study comprised 286 case subjects (174 males, 112 females; median age 65 years) with incident, histologically confirmed colon (n = 149) or rectal (n = 137) cancer, and 550 control subjects (269 males, 281 females; median age 59 years) admitted to the same University Hospital for a wide spectrum of acute non-neoplastic conditions. Dietary habits were investigated using a validated food frequency questionnaire, including questions on 79 foods or recipes and on individual fat intake pattern. Multivariate odds ratios (OR) were obtained after allowance for age, sex, education, physical activity and energy intake. RESULTS: The risk of colon and rectal cancer increased with total energy intake (OR in highest and lowest tertile, 2.0 and 2.2, respectively). There was no significant relation with starches or proteins, a significant inverse relation with sugars (OR for the highest tertile, 0.5), a direct trend in risk of borderline significance for saturated fats (OR = 1.4 for the highest tertile), and significant inverse trends for monounsaturated (OR = 0.6) and polyunsaturated fats (OR = 0.6). CONCLUSIONS: These findings confirm that energy intake is directly related to colorectal cancer risk, and that different types of fat may have different roles in colorectal carcinogenesis.

Phase I trial of oral green tea extract in adult patients with solid tumors.

Pisters KM, Newman RA, Coldman B, et al.

J Clin Oncol. 2001 Mar 15; 19(6):1830-8.

PURPOSE: This trial was designed to determine the maximum-tolerated dose, toxicity, and pharmacology of oral green tea extract (GTE) once daily or three times daily. PATIENTS AND METHODS: Cohorts of three or more adult cancer patients were administered oral GTE with water after meals one or three times daily for 4 weeks, to a maximum of 6 months, depending on disease response and patient tolerance. Pharmacokinetic analyses were encouraged but optional. RESULTS: Dose levels of 0.5 to 5.05 g/m(2) qd and 1.0 to 2.2 g/m(2) tid were explored. A total of 49 patients were studied. Patient characteristics: median age, 57 years (range, 27 to 77 years); 23 patients were women (47%); 98% had a Zubrod PS of 1%; 98% had PS of 1; and 21 had non-small-cell lung, 19 had head & neck cancer, three had mesothelioma, and six had other. Mild to moderate toxicities were seen at most dose levels and promptly reversed on discontinuation of GTE. Dose-limiting toxicities were caffeine related and included neurologic and gastrointestinal effects. The maximum-tolerated dose was 4.2 g/m(2) once daily or 1.0 g/m(2) three times daily. No major responses occurred; 10 patients with stable disease completed 6 months of GTE. Pharmacokinetic analyses found accumulation of caffeine levels that were dose dependent, whereas epigallocatechin gallate levels did not accumulate nor appear dose related. CONCLUSION: A dose of 1.0 g/m(2) tid (equivalent to 7 to 8 Japanese cups [120 mL] of green tea three times daily) is recommended for future studies. The side effects of this preparation of GTE were caffeine related. Oral GTE at the doses studied can be taken safely for at least 6 months

Dietary fiber and distal colorectal adenoma in men.

Platz EA, Giovannucci E, Rimm EB, et al.

Cancer Epidemiol Biomarkers Prev. 1997 Sep; 6(9):661-70.

We evaluated the relation of specific sources and components of fiber with diagnosis of distal colon (n = 531) or rectal (n = 159) adenomatous polyps or hyperplastic (n = 327) polyps in the Health Professionals Follow-up Study. We studied 16,448 men free of cancer or polyps in 1986, who underwent endoscopy in 1986-1994, and who provided diet and medical history. Relative risks (RRs) and 95% confidence intervals (CIs) adjusted using multiple logistic regression were calculated. We observed a modest reduced risk of distal colon adenoma with increasing intake of fiber from fruit (P-trend = 0.03) but not cereals or vegetables. The RR comparing the highest (median, 8.4 g/day) to lowest (1.3 g/day) quintile of fruit fiber intake was 0.81 (95% CI, 0.59-1.11). Soluble fiber, but not insoluble fiber, appeared to be inversely associated with distal colon adenoma (P-trend = 0.007). Comparing extreme quintiles (9.4 versus 3.4 g/day soluble fiber), the RR was 0.69 (95% CI, 0.46-1.03). Polyps detected in 1986 or later among men also with a negative endoscopy before 1986 may be considered to be "incident," with diet report corresponding more closely to time of polyp development. For "incident" cases (n = 130), the relation between soluble fiber and distal colon adenoma was strengthened (extreme quintiles RR, 0.27; 95% CI, 0.11-0.66; P-trend = 0.003), whereas for "prevalent" cases (n = 401), we found no association. No consistent relation between fiber and rectal adenomas or hyperplastic polyps was observed. These results suggest that soluble fiber may be particularly important in reducing risk of adenomatous polyps of the distal colon and support national dietary guidelines of increasing fruit consumption

Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex.

Plummer SM, Holloway KA, Manson MM, et al.

Oncogene. 1999 Oct 28; 18(44):6013-20.

Colorectal cancer is a major cause of cancer deaths in Western countries, but epidemiological data suggest that dietary modification might reduce these by as much as 90%. Cyclo-oxygenase 2 (COX2), an inducible isoform of prostaglandin H synthase, which mediates prostaglandin synthesis during inflammation, and which is selectively overexpressed in colon tumours, is thought to play an important role in colon carcinogenesis. Curcumin, a constituent of turmeric, possesses potent anti-inflammatory activity and prevents colon cancer in animal models. However, its mechanism of action is not fully understood. We found that in human colon epithelial cells, curcumin inhibits COX2 induction by the colon tumour promoters, tumour necrosis factor alpha or fecapentaene-12. Induction of COX2 by inflammatory cytokines or hypoxia-induced oxidative stress can be mediated by nuclear factor kappa B (NF-kappaB). Since curcumin inhibits NF-kappaB activation, we examined whether its chemopreventive activity is related to modulation of the signalling pathway which regulates the stability of the NF-kappaB-sequestering protein, IkappaB. Recently components of this pathway, NF-kappaB-inducing kinase and IkappaB kinases, IKKalpha and beta, which phosphorylate IkappaB to release NF-kappaB, have been characterised. Curcumin prevents phosphorylation of IkappaB by inhibiting the activity of the IKKs. This property, together with a long history of consumption without adverse health effects, makes curcumin an important candidate for consideration in colon cancer prevention

Mutated p53 gene is an independent adverse predictor of survival in colon carcinoma.

Pricolo VE, Finkelstein SD, Hansen K, et al.

Arch Surg. 1997 Apr; 132(4):371-4.

OBJECTIVE: To evaluate the impact of p53 gene mutations on long-term survival in patients with intermediate stage carcinoma of the colon. DESIGN: Retrospective cohort study; median follow-up of 87 months. SETTING: Tertiary care academic medical center. PATIENTS: Mutational analysis was conducted in a single institution in 141 consecutive patients with resected stage II (n = 71) and stage III (n = 70) colon carcinoma. Archival pathology specimens were analyzed for point mutations of exons from the p53 gene by means of amplification and direct sequencing by polymerase chain reaction. MAIN OUTCOME MEASURES: The impact of p53 mutations and of adverse histopathologic features (i.e., poor differentiation, lymphovascular invasion, or mucin production) on patient survival. RESULTS: Median overall survival was 64 months (95 months for patients with stage II and 34 months for patients with stage III colon carcinoma; P = .001). Presence of a p53 mutation was the single most important risk factor associated with poorer survival in both patients with stage II (P = .02) and stage III colon carcinoma (P = .006) throughout the follow-up period. A p53 mutation increased the risk of death by 2.82 times in patients with stage II and by 2.39 times in patients with stage III colon carcinoma. There was an additive effect on the cumulative risk of death between p53 mutations and adverse histopathologic variables. CONCLUSIONS: The presence of p53 mutations carries an independent adverse prognostic value in colon cancer. These findings imply that the applicability of mutational analysis in clinical practice is likely to affect therapeutic choices in the future

Prophylactic colectomy or surveillance for chronic ulcerative colitis? A decision analysis.

Provenzale D, Kowdley KV, Arora S, et al.

Gastroenterology. 1995 Oct; 109(4):1188-96.

BACKGROUND & AIMS: The treatment of patients with long-standing ulcerative colitis involving the entire colon is controversial. The aim of this study was to examine the effectiveness of surveillance colonoscopy or prophylactic colectomy on colon cancer mortality in patients with chronic ulcerative colitis. METHODS: Using decision analysis, computer cohort simulation of patients with ulcerative colitis was performed to evaluate 17 strategies including no colonoscopic surveillance, surveillance at varying intervals, and prophylactic proctocolectomy with ileal pouch-anal anastomosis. The model examined which biopsy results (low-grade dysplasia, high-grade dysplasia, or cancer) should lead to proctocolectomy and ileal pouch-anal anastomosis. Published data on the incidence of cancer with ulcerative colitis, the sensitivity and specificity of colonoscopy with biopsy, the risks of colonoscopy and surgery, and the prognosis with colon cancer were used. RESULTS: For a 30-year-old patient with pancolitis for 10 years, the model suggests that prophylactic colectomy would increase life expectancy by 2-10 months compared with surveillance and by 1.1-1.4 years compared with no surveillance. Surveillance would improve life expectancy by 7 months to 1.2 years compared with no surveillance. In sensitivity analysis, results were most affected by the cumulative incidence of cancer in patients with chronic ulcerative colitis. CONCLUSIONS: Either surveillance or prophylactic colectomy should increase life expectancy in patients with ulcerative colitis

Blood selenium and glutathione peroxidase status in patients with colorectal cancer.

Psathakis D, Wedemeyer N, Oevermann E, et al.

Dis Colon Rectum. 1998 Mar; 41(3):328-35.

PURPOSE: It is still controversial whether a low selenium level and a reduced activity of the selenium-dependent enzyme, glutathione peroxidase, in blood are associated with an increased risk and poor prognosis of cancer in humans. This study evaluates whether colorectal cancer patients have lower serum selenium and glutathione peroxidase levels than a gender-matched and age-matched control group and whether there is a correlation to clinical data and prognosis. METHODS: In a retrospective study, serum selenium and glutathione peroxidase activity of 106 patients with colorectal cancer were determined. Clinical data were provided by our long-term follow-up program for colorectal cancer patients. RESULTS: Patients with a selenium level <70 microg/l had a significantly lower mean survival time and a lower cumulative cancer-related survival rate than patients with a selenium level >70 microg/l (P = 0.0009). When considering the different tumor stages, a decline of the mean selenium level in the T4 carcinoma group was found in the analysis of variance (P < 0.05). The lowest selenium level was found for patients with advanced tumor disease and in a preoperative situation, ie., high tumor burden. In comparison with the control group, the cancer group showed a significant reduction of serum glutathione peroxidase activity (P < 0.01) but no significant difference in selenium level. CONCLUSIONS: These results support the hypothesis of an association between low selenium level and advanced tumor disease. From our data, it cannot be decided whether this phenomenon is more likely to be a consequence or a causative factor for development and course of the disease

Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study.

Pufulete M, Al Ghnaniem R, Leather AJ, et al.

Gastroenterology. 2003 May; 124(5):1240-8.

BACKGROUND & AIMS: Low folate intake may increase risk for colorectal cancer by inducing DNA hypomethylation. This study reports the influence of folate status, DNA methylation, and polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677C-->T and 1298A-->C), methionine synthase (MS 2756A-->G), and cystathionine-beta-synthase (CBS 844ins68) on risk for developing colorectal neoplasia. METHODS: Thirty-five patients with adenoma, 28 patients with cancer, and 76 controls were recruited for a case control study. Recruitment consent rate was 98%. Blood samples were obtained for determination of blood folates, vitamin B(12), homocysteine, DNA methylation, and genotypes. Tissue biopsy samples were obtained at colonoscopy for determination of DNA methylation in colonic mucosa. Folate status was assessed by constructing a score from estimates of dietary intake and serum and erythrocyte folate. RESULTS: Cancer patients had 26% lower folate status (95% confidence interval [CI]: 6% to 44%, P = 0.01) and 21% lower serum vitamin B(12) concentration (95% CI: -38% to 1%, P = 0.06) compared with controls. [(3)H] methyl incorporation into colonic DNA was 26% higher in patients with adenoma (95% CI: 8% to 56%, P = 0.009) and 30% higher in patients with cancer (95% CI: -3% to 48%, P = 0.08) compared with controls. High folate status was associated with decreased risk for cancer (P = 0.01 for trend). Colonic and leukocyte DNA hypomethylation were associated with increased risk for adenoma (P = 0.02 and P = 0.01 for trend, respectively) and a nonsignificantly increased risk for cancer (P = 0.09 and P = 0.08 for trend, respectively). CONCLUSIONS: Low folate status and DNA hypomethylation are associated with colorectal neoplasia

Effect of different curcumin dosages on human gall bladder.

Rasyid A, Rahman AR, Jaalam K, et al.

Asia Pac J Clin Nutr. 2002; 11(4):314-8.

Our previous study demonstrated that curcumin, an active compound of Curcuma xanthorrhiza and C. domestica, produces a positive cholekinetic effect. A 20 mg amount of curcumin is capable of contracting the gall bladder by up to 29% within an observation time of 2 h. The aim of the current study was to define the dosage of curcumin capable of producing a 50% contraction of the gall bladder, and to determine if there is a linear relationship between doubling the curcumin dosage and the doubling of gall bladder contraction. A randomised, single-blind, three-phase, crossover-designed examination was carried out on 12 healthy volunteers. Ultrasonography was carried out serially to measure the gall bladder volume. The data obtained was analysed by analysis of variance (ANOVA). The fasting volumes of gall bladders were similar (P > 0.50), with 17.28 +/- 5.47 mL for 20 mg curcumin, 18.34 +/- 3.75 mL for 40 mg and 18.24 +/- 3.72 mL for 80 mg. The percentage decrease in gall bladder volume 2 h after administration of 20, 40 and 80 mg was 34.10 +/- 10.16, 51.15 +/- 8.08 and 72.25 +/- 8.22, respectively, which was significantly different (P < 0.01). On the basis of the present findings, it appears that the dosage of cucumin capable of producing a 50% contraction of the bladder was 40 mg. This study did not show any linear relationship between doubling curcumin dosage and the doubling of gall bladder contraction

Metabolic epidemiology of colon cancer: effect of dietary fiber on fecal mutagens and bile acids in healthy subjects.

Reddy BS, Sharma C, Simi B, et al.

Cancer Res. 1987 Jan 15; 47(2):644-8.

Because of potential significance of fecal mutagens and secondary bile acids in the pathogenesis of colonic cancer and of inverse association between dietary fiber and colonic cancer risk, the effect of dietary wheat and rye fiber on fecal mutagenic activity and bile acid levels was studied in 15 healthy men and women who were consuming high fat/moderately low fiber diets and excreting high levels of fecal mutagens and bile acids. Each participant provided two 24-h stool specimens and a 3-day diet record while consuming their normal diet (control). All subjects were then asked to consume their normal diet plus 11 g of supplemental fiber per day in the form of whole grain bread for 4 weeks. During the last week of diet intervention, each subject provided two 24-h stool specimens and a 3-day dietary record. Fecal samples collected from both periods were analyzed for bile acids and for mutagens using Salmonella typhimurium strains TA98 and TA100 with and without microsomal activation. The concentration of fecal secondary bile acids was significantly lower during the fiber supplemental period in all subjects. Fiber supplementation also inhibited the fecal mutagenic activity in TA100 and TA98 with and without microsomal activation. Thus, the increased fiber intake in the form of whole wheat and rye bread may reduce the production and/or excretion of fecal mutagens and decrease the concentration of fecal secondary bile acids in humans

Novel approaches for colon cancer prevention by cyclooxygenase-2 inhibitors.

Reddy BS, Rao CV.

J Environ Pathol Toxicol Oncol. 2002; 21(2):155-64.

During recent years, multidisciplinary studies in epidemiology and molecular biology, as well as preclinical studies, have contributed much to our understanding of the etiology of colorectal cancer; more importantly they have enabled us to approach its prevention. An impressive body of epidemiological data suggests an inverse relationship between colorectal cancer risk and regular use of nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin. Clinical trials with NSAIDs have demonstrated that NSAID treatment caused regression of preexisting colon adenomas in patients with familial adenomatous polyposis. Preclinical efficacy studies have provided compelling evidence that several phytochemicals with antiinflammatory properties and NSAIDs act to retard, block, or reverse colon carcinogenesis. Equally exciting are opportunities for effective chemoprevention with selective cyclooxygenase-2 (COX-2) inhibitors including celecoxib and rofecoxib in a variety of preclinical models of colon cancer. Naturally occurring COX-2 inhibitors such as curcumin and certain phytosterols have been proven to be effective as chemopreventive agents against colon carcinogenesis with minimal gastrointestinal toxicity. Multistep process of carcinogenesis has provided substantial insights into the mechanisms by which naturally occurring and synthetic antiinflammatory agents modulate these events leading to suppression of tumorigenesis. Growing knowledge in this area has brought about innovative approaches using a combination of agents with different modes of action as a means of increasing efficacy and minimizing toxicity. The natural history of colorectal cancer, from dysplastic aberrant crypts to adenomas and adenocarcinomas, offers multiple opportunities for assessment and intervention. Of further importance would be to identify molecular targets that are critical in the growth and survival of the malignant colorectal cell and are modulated by NSAIDs and COX-2 inhibitors

Curcumin is a non-competitive and selective inhibitor of phosphorylase kinase.

Reddy S, Aggarwal BB.

FEBS Lett. 1994 Mar 14; 341(1):19-22.

Recently, we reported that curcumin (diferuloylmethane) inhibits the growth of several different kinds of tumor cells. In order to investigate the mechanism of this inhibition, we examined the effects of curcumin on different protein kinases: highly purified protein kinase A (PkA), protein kinase C (PkC), protamine kinase (cPK), phosphorylase kinase (PhK), autophosphorylation-activated protein kinase (AK) and pp60c-src tyrosine kinase. While all kinases tested were inhibited by curcumin, only PhK was completely inhibited at relatively lower concentrations. At around 0.1 mM curcumin, PhK, pp60c-src, PkC, PkA, AK, and cPK were inhibited by 98%, 40%, 15%, 10%, 1%, and 0.5%, respectively. Lineweaver-Burk plot analysis indicated that curcumin is a non-competitive inhibitor of PhK with a Ki of 0.075 mM. Overall, our results indicate that curcumin is a potent and selective inhibitor of phosphorylase kinase, a key regulatory enzyme involved in the metabolism of glycogen. This has important implications for the anti-proliferative effects of curcumin

Nonsteroidal anti-inflammatory drug use and protection against colorectal cancer in women 1.

Reeves MJ, Newcomb PA, Trentham-Dietz A, et al.

Cancer Epidemiol Biomarkers Prev. 1996 Dec; 5(12):955-60.

Several epidemiological studies have identified an association between nonsteroidal anti-inflammatory drug (NSAID) use and colorectal cancer risk in women. We examined this association in a population-based case-control study in Wisconsin women. Between 1991 and 1992, 184 women ages 40-74 years with colorectal cancer were identified through the statewide cancer registry and 293 population-based control women were randomly selected via telephone. Regular NSAID use was defined as at least twice weekly for 12 months or longer. After adjusting the data for age, controls were more likely than cases to report regular NSAID use (38 versus 27%). Following adjustment for age, prior sigmoidoscopy use, family history of large bowel cancer, and body mass index, women who regularly used NSAIDs were approximately one-third less likely to be diagnosed with colorectal cancer compared to women who did not use NSAIDs [odds ratio (OR), 0.65; 95% confidence interval (CI), 0.40-1.03]. A statistically significant effect of duration of use was identified, although the ORs did not show a consistent trend. No significant effect of frequency of NSAID use was observed. When the type of NSAID used was examined (aspirin or nonaspirin), subjects who used nonaspirin compounds had a statistically significantly lower risk of colorectal cancer (OR, 0.43; 95% CI, 0.20-0.89), compared to nonusers, whereas aspirin users had only a small, nonsignificant reduction in cancer risk (OR, 0.79; 95% CI, 0.46-1.36). These data add support to the hypothesis that regular NSAID use is associated with lower colorectal cancer risk in women and suggest that the type of NSAID used may be important

Histamine content in colorectal cancer. Are there sufficient levels of histamine to affect lymphocyte function?

Reynolds JL, Akhter J, Adams WJ, et al.

Eur J Surg Oncol. 1997 Jun; 23(3):224-7.

Histamine has been found to stimulate growth of colorectal cancer in vitro and in vivo. Histamine has also been found to inhibit lymphocyte activity in vitro at concentrations greater than 10(-7) M. The aim of our study was to determine if the histamine concentrations in human colorectal cancer were sufficient to achieve these effects. We measured the histamine content in 31 colorectal cancer specimens using a radioenzymatic assay. Results were expressed as microgram histamine per gram of fresh tissue weight. Recovery and reproducibility studies were also carried out. The median histamine concentration in colorectal cancer tissue was 8.4 micrograms/g [7.6 x 10(-5)M], ranging from 0.3 microgram/g to 20.6 micrograms/g. The high concentration of histamine in colon cancer is enough to be locally immunosuppressive

Inflammation and colorectal cancer: IBD-associated and sporadic cancer compared.

Rhodes JM, Campbell BJ.

Trends Mol Med. 2002 Jan; 8(1):10-6.

Ulcerative colitis and colonic Crohn's disease (together known as inflammatory bowel disease or IBD) are both associated with increased risk for colorectal cancer. Although it is customary to emphasize differences in the biology of IBD-associated and sporadic colon cancer, we believe these are far outweighed by the similarities. These similarities suggest that they might have similar pathogenic mechanisms. Because the normal colon is arguably in a continual state of low-grade inflammation in response to its microbial flora, it is reasonable to speculate that both IBD-associated and sporadic colon cancer might be the consequence of bacteria-induced inflammation

Altered eicosanoid levels in human colon cancer 1.

Rigas B, Goldman IS, Levine L.

J Lab Clin Med. 1993 Nov; 122(5):518-23.

Eicosanoids may participate in colon carcinogenesis, as evidenced from work in animal tumor models showing prevention of colon cancer by inhibitors of their synthesis and epidemiologic studies demonstrating reduced risk of colon cancer in long-term users of aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs). The levels of prostaglandin E2 (PGE2), PGF2 alpha, PGI2, thromboxane A2 (TXA2), and leukotriene B4 (LTB4), which represent the cyclooxygenase and 5-lipoxygenase pathways, were determined in 21 pairs of surgically excised human colon cancer and histologically normal mucosa samples 5 to 10 cm away from the tumor. The levels of PGE2 were elevated in colon cancer samples as compared with histologically normal mucosa samples distant from the cancer (p < 0.01), whereas levels of prostacyclin (PGI2) were decreased (p < 0.05). The differences in the levels of PGF2 alpha, TXA2, and LTB4 between normal and malignant tissue were not statistically significant. No statistically significant association was found between the level of each of the eicosanoids assayed and Dukes' stage of colon cancer. These findings, confirming and extending earlier work from tumors and cell culture, suggest that the protective effect of aspirin and other NSAIDs in the development of human colon cancer may be mediated, at least in part, through their inhibition of arachidonic acid metabolism by cyclooxygenase

Histamine receptors in an experimental mammary carcinoma.

Rivera ES, Davio CA, Venturino A, et al.

Biomed Pharmacother. 1994; 48(8-9):399-406.

An experimental mammary carcinoma was induced in Sprague-Dawley rats by the ip administration of N-nitroso-N-methylurea (NMU) in three doses of 50 mg/kg. In order to study the expression of histamine receptors in these experimental tumors, the presence of specific binding sites for histamine was studied. Using [3H]-histamine as a radioligand, two specific binding sites were characterized on the cell membrane. The first site, of high affinity, Kd = 4 +/- 2 nM, was further characterized as an H2 type using [3H]-cimetidine and [3H]-tiotidine as radioligands and by displacement experiments with different histamine agonists and antagonists. The second one of low affinity, Kd = 35 +/- 14 nM, needs further characterization. The determination of cAMP levels showed that histamine and the H2 agonist dimaprit, produced a significant decrease in the nucleotide concentration 6 minutes after stimulation, in a response that was specifically abolished by H2 antagonists. Based on these results, we conclude that neoplastic cells from NMU induced tumors express H2 histamine membrane receptors which are coupled to a transductional pathway different from cAMP production, which may be involved in the regulation of tumor growth

Histamine-induced suppressor factor (HSF): further studies on the nature of the stimulus and the cell which produces it.

Rocklin RE, Greineder DK, Melmon KL.

Cell Immunol. 1979 May; 44(2):404-15.

Oral calcium suppresses increased rectal epithelial proliferation of persons at risk of colorectal cancer 1158.

Rozen P, Fireman Z, Fine N, et al.

Gut. 1989 May; 30(5):650-5.

Dietary calcium may inhibit colonic carcinogenesis promoted by high fat, phosphate, and low fibre diets. In persons at risk for colon cancer oral calcium supplements significantly suppress increased rectal epithelial proliferation. This was studied in a cohort of 35 volunteers: 26 first degree relatives of colorectal cancer patients and nine who had had colonic adenomas (mean age 51.6 years, 17 (49%) men, all negative for large bowel neoplasia). 1.25-1.5 g elemental calcium was given in divided daily doses for three months. Rectal pinch biopsies were taken without bowel preparation, before and mean 8.4 weeks during and 7.2 weeks after treatment and incubated with tritiated thymidine. The mean number of labelled cells, as a ratio of the total number of crypt cells (labelling index-LI), and their crypt position, were determined. The mean number of labelled cells decreased during treatment by 29%, especially in the basal three-fifths of crypts. There was also a significant 10% increase in mean number of crypt cells during treatment. [Mean LI decreased by 36% (p less than 0.001) during calcium treatment and almost returned to basal values after cessation.] If a raised LI is a marker of potential malignancy and a randomised clinical trial confirms that calcium suppresses it, dietary intervention studies in high risk persons are indicated

Calcium supplements interact significantly with long-term diet while suppressing rectal epithelial proliferation of adenoma patients.

Rozen P, Lubin F, Papo N, et al.

Cancer. 2001 Feb 15; 91(4):833-40.

BACKGROUND: Calcium supplements to the western-style diet may reduce the risk for colorectal neoplasia. Using rectal epithelial proliferation (REP) measurements as a biomarker of response to intervention, the authors evaluated the effects of 1-year calcium supplementation in adenoma patients and its possible interactions with the patients' dietary and lifestyle habits. METHODS: Consenting adenoma patients, without a family history of colorectal neoplasia, were randomly selected to receive 3.75 g calcium carbonate (1.5 g Ca2+) daily or to receive no treatment. All had their long-term dietary and lifestyle habits assessed and their REP labeling index (LI) evaluated before and at end of follow-up. The change in LI was compared between groups, and statistical associations were examined between mean nutrient consumption and treatment effect and between lifestyle and treatment effect. RESULTS: Fifty-two adenoma patients (33 treated and 19 untreated) completed intervention and follow-up. There were no significant differences between study groups in age, weight, cigarette smoking, or medication use. The LI decreased in 58% of calcium-intervened patients and in only 26% of nonintervened patients (P = 0.04); the mean LI x 100 (+/- standard deviation) of the former fell from 5.04 +/- 1.93 to 4.54 +/- 1.58, and rose from 4.32 +/- 1.58 to 4.93 +/- 1.58 in the latter (P = 0.04). A lower fat, a higher carbohydrate, fiber, or fluid intake each interacted with the calcium supplementation to decrease the LI (P = 0.02, 0.001, 0.02, and 0.08, respectively). CONCLUSIONS: Long-term calcium supplements significantly suppressed REP in adenoma patients, and long-term dietary habits contributed to this effect. Patient diet should be assessed when researchers use REP as a biomarker in calcium chemoprevention studies. Study results indicated that relevant dietary counseling may be useful in addition to calcium supplements in persons at increased risk for colorectal neoplasia

Decrease in serum levels of vitamin A and zeaxanthin in patients with colorectal polyp.

Rumi G, Jr., Szabo I, Vincze A, et al.

Eur J Gastroenterol Hepatol. 1999 Mar; 11(3):305-8.

OBJECTIVE: Several retrospective and prospective epidemiological investigations have demonstrated that a diet rich in carotenoids could prevent the development of pre-cancerous and neoplastic lesions of the digestive tract. The aim of this examination was to analyse the correlation between colorectal polyps with different histological classifications and serum carotenoid levels. DESIGN AND METHODS: A 10 ml blood sample was taken from all of the patients after the colonoscopic diagnosis. The serum levels of vitamin A, lutein, zeaxanthin, alpha- and beta-cryptoxanthin, alpha- and beta-carotene were measured in patients with adenomatous colorectal polyp (n = 59, 35 males, 24 females) by high-pressure liquid chromatography (HPLC) and compared with those in healthy subjects (n = 20, 10 males, 10 females). The patients were separated into four groups depending on their histological findings. RESULTS: The serum levels of vitamin A and zeaxanthin were significantly lower in all patients with polyps (vitamin A: 0.913 +/- 0.112 micromol/l, zeaxanthin: 0.071 +/- 0.012 micromol/l) than in the control healthy group (vitamin A: 2.036 +/- 0.354 micromol/l, zeaxanthin: 0.138 +/- 0.048 micromol/l). The lowest levels were found in patients with focal adenocarcinoma in the polyp. There were no significant differences in the serum levels of other carotenoids. The serum levels of cholesterol, haemoglobin, total protein and albumin were normal in these patients. CONCLUSIONS: There are close and inverse correlations between the serum level of carotenoids and colorectal polyps with different histological grades. The low mean carotenoid levels in patients with adenocarcinoma in the polyp indicate that deficiency of carotenoids may be an important factor in the development of colorectal cancer

Body size and colorectal-cancer risk 1.

Russo A, Franceschi S, La Vecchia C, et al.

Int J Cancer. 1998 Oct 5; 78(2):161-5.

Individuals whose energy intake exceeds expenditure are at increased risk of colorectal cancer. To determine whether body-size measurements at different ages were risk factors for cancer of the colon-rectum, we carried out a hospital-based case-control study in 6 Italian areas, 2 of which were in the South. Interviews were conducted with 1,217 subjects of both genders with incident histologically confirmed cancer of the colon, 726 with cancer of the rectum, and 4,136 controls hospitalized for acute, non-neoplastic, non-digestive conditions. The questionnaire included information on sociodemographic factors, and physical activity, a validated dietary history, height, weight at diagnosis and at 12, 30 and 50 years of age and waist-to-hip ratio (WHR). After allowance for education, physical activity, energy intake, family history of colorectal cancer and recent change in weight, the body-mass index (BMI) was significantly associated with colorectal-cancer-risk in men (odds ratio, OR, in highest vs. lowest quintile = 1.7; 95% confidence interval, CI, 1.3-2.3), but not in women (corresponding OR = 0.9; 95% CI, 0.7-1.2). Cases of both gender tended to have higher BMI than controls in adolescence, young adulthood and middle age. Height appeared unrelated to risk. In women, but not in men, WHR was positively associated with risk, independently of BMI (OR for > or = 0.90 vs. < or = 0.81 = 1.6; 95% CI; 1.2-2.1). Thus, excessive weight predicts colorectal-cancer risk in men, whereas abdominal obesity (i.e., a high WHR) represents a more reliable risk indicator in women

Plasma selenium levels and the risk of colorectal adenomas.

Russo MW, Murray SC, Wurzelmann JI, et al.

Nutr Cancer. 1997; 28(2):125-9.

Previous research has suggested that selenium may protect against the development of colorectal neoplasia. We examined the potential chemopreventive properties of selenium against colorectal adenomas while controlling for a number of dietary and life-style factors. We conducted a cross-sectional study among patients referred for colonoscopy to University of North Carolina Hospitals. Cases had one or more pathologically confirmed adenomas, and noncases had none. Plasma selenium levels were determined using graphite furnace atomic absorption spectrometry with Zeeman background correction and platform technique. Odds ratios were calculated using logistic regression analysis adjusting for potential confounders. The mean plasma selenium concentrations for cases (n = 37) and noncases (n = 36) were 107 and 120 micrograms/l, respectively (p = 0.06). Those in the fourth quartile of plasma selenium level had 0.24 times the risk (95% confidence interval = 0.06-1.04) for colorectal adenomas of those in the first quartile. The adjusted odds ratio for colorectal adenomas was 0.58 (95% confidence interval = 0.31-1.08) for a 30 microgram/l increase in plasma selenium level. Lower plasma selenium levels were associated with multiple adenomas but not with adenoma size or location. These data support a protective effect of selenium against colorectal adenomas after adjustment for possible confounders. Selenium might be a potentially useful chemopreventive agent for colorectal neoplasia

Flavonoids uptake and their effect on cell cycle of human colon adenocarcinoma cells (Caco2).

Salucci M, Stivala LA, Maiani G, et al.

Br J Cancer. 2002 May 20; 86(10):1645-51.

Green tea, mainly through its constituents epigallocatechin gallate, epigallocatechin, epicatechin gallate and epicatechin, has demonstrated anticarcinogenic activity in several animal models, including those for skin, lung and gastro-intestinal tract cancer, although less is known about colorectal cancer. Quercetin, the major flavonoid present in vegetables and fruit, exerts potential anticarcinogenic effects in animal models and cell cultures, but less is known about quercetin glucosides. The objectives of this study were to investigate (i) the antioxidant activity of the phenolic compounds epicatechin, epigallocatechin gallate, gallic acid and quercetin-3-glucoside; (ii) the cytotoxicity of different concentrations of epicatechin, epigallocatechin gallate, and gallic acid; (iii) the cellular uptake of epicatechin, epigallocatechin gallate, gallic acid and quercetin-3-glucoside and (iv) their effect on the cell cycle. Human colon adenocarcinoma cells were used as experimental model. The results of this study indicate that all dietary flavonoids studied (epicatechin, epigallocatechin gallate, gallic acid and quercetin-3-glucoside) show a significant antioxidant effect in a chemical model system, but only epigallocatechin gallate or gallic acid are able to interfere with the cell cycle in Caco2 cell lines. These data suggest that the antioxidant activity of flavonoids is not related to the inhibition of cellular growth. From a structural point of view, the galloyl moiety appears to be required for both the antioxidant and the antiproliferative effects

Genistein and curcumin block TGF-beta 1-induced u-PA expression and migratory and invasive phenotype in mouse epidermal keratinocytes.

Santibanez JF, Quintanilla M, Martinez J.

Nutr Cancer. 2000; 37(1):49-54.

Transforming growth factor-beta 1 (TGF-beta 1) stimulates migration/invasion of mouse transformed keratinocytes and increases urokinase (u-PA) expression/secretion. In this report, we analyzed the biological behavior of two naturally occurring inhibitors of protein tyrosine kinases, genistein and curcumin, that could abrogate the enhancement of u-PA levels induced by TGF-beta 1 in transformed keratinocytes. Our results showed that genistein and curcumin blocked this response in a dose-dependent manner and also inhibited the TGF-beta 1-induced synthesis of fibronectin, an early responsive gene to the growth factor. Both compounds also reduced TGF-beta 1-stimulated cell migration and invasiveness. These results suggest that a tyrosine kinase-signaling pathway should be involved in TGF-beta 1-mediated increased malignancy of transformed keratinocytes and that genistein and curcumin could play an important role in inhibiting tumor progression

Anti-proliferative effect of resveratrol, a natural component of grapes and wine, on human colonic cancer cells.

Schneider Y, Vincent F, Duranton B, et al.

Cancer Lett. 2000 Sep 29; 158(1):85-91.

Resveratrol, a natural polyphenolic phytoalexine present in grapes and wines, has been reported to exert a variety of important pharmacological effects. We investigated the effects of resveratrol on the growth and polyamine metabolism of CaCo-2 human colon cancer cells. Treatment of the CaCo-2 cells with 25 microM resveratrol caused a 70% growth inhibition. The cells accumulated at the S/G2 phase transition of the cell cycle. No signs of cytotoxicity or apoptosis were detected. Resveratrol caused a significant decrease of ornithine decarboxylase (ODC) activity, a key enzyme of polyamine biosynthesis, which is enhanced in cancer growth. ODC inhibition resulted in the reduction of the intracellular putrescine content, indicating that polyamines might represent one of several targets involved in the anti-proliferative effects of resveratrol

Increased blood glucose and insulin, body size, and incident colorectal cancer 1.

Schoen RE, Tangen CM, Kuller LH, et al.

J Natl Cancer Inst. 1999 Jul 7; 91(13):1147-54.

BACKGROUND: Abdominal obesity--an elevated level of visceral adipose tissue--has been linked to colorectal cancer. Furthermore, elevated levels of visceral adipose tissue have been associated with hyperinsulinemia, and insulin is a growth factor in the colon. We assessed whether waist circumference, a surrogate measure of visceral adipose tissue, and metabolic parameters associated with visceral adipose tissue were related to colorectal cancer. METHODS: In the Cardiovascular Health Study cohort, we examined the relationship of baseline measurements of body size, glucose, insulin, and lipoproteins to incident colorectal cancer. All P values are two-sided. RESULTS: Among 5849 participants, 102 incident cases of colorectal cancer were identified. Individuals in the highest quartile of fasting glucose had a nearly twofold increased risk of colorectal cancer (relative risk [RR] = 1.8; 95% confidence interval [CI] = 1.0-3.1), and the linear trend RR (LT RR = 1.2; 95% CI = 1.0-1.5) for fasting glucose level was statistically significant (P =. 02). Glucose and insulin levels 2 hours after oral glucose challenge also exhibited statistically significant associations with colorectal cancer (2-hour glucose levels: RR = 2.4 [95% CI = 1.2-4. 7]/LT RR = 1.3 [95% CI = 1.0-1.6; P =.02]; 2-hour insulin levels: RR = 2.0 [95% CI = 1.0-3.8]/LT RR = 1.2 [95% CI = 1.0-1.5; P =.04]). Analysis of fasting insulin levels suggested a threshold effect, with values above the median associated with colorectal cancer (RR = 1.6; 95% CI = 1.1-2.4; P =.02). Higher levels of waist circumference were also statistically significantly associated with colorectal cancer (RR = 1.9; 95% CI = 1.1-3.3; P =.02). CONCLUSIONS: These data provide, to our knowledge, the first direct evidence of an association between elevated visceral adipose tissue level, its associated metabolic effects, and colorectal cancer

Chronic inflammation and cancer.

Shacter E, Weitzman SA.

Oncology (Huntingt). 2002 Feb; 16(2):217-26, 229.

A substantial body of evidence supports the conclusion that chronic inflammation can predispose an individual to cancer, as demonstrated by the association between chronic inflammatory bowel diseases and the increased risk of colon carcinoma. Chronic inflammation is caused by a variety of factors, including bacterial, viral, and parasitic infections, chemical irritants, and nondigestible particles. The longer the inflammation persists, the higher the risk of associated carcinogenesis. This review describes some of the underlying causes of the association between chronic inflammation and cancer. Inflammatory mediators contribute to neoplasia by inducing proneoplastic mutations, adaptive responses, resistance to apoptosis, and environmental changes such as stimulation of angiogenesis. All these changes confer a survival advantage to a susceptible cell. In this article, we discuss the contribution of reactive oxygen and nitrogen intermediates, prostaglandins, and inflammatory cytokines to carcinogenesis. A thorough understanding of the molecular basis of inflammation-associated neoplasia and progression can lead to novel approaches to the prevention and treatment of cancer

Curcumin exerts multiple suppressive effects on human breast carcinoma cells.

Shao ZM, Shen ZZ, Liu CH, et al.

Int J Cancer. 2002 Mar 10; 98(2):234-40.

In our study, we present experimental evidence suggesting that curcumin exerts multiple different suppressive effects on human breast carcinoma cells in vitro. Our experiments demonstrate that curcumin's antiproliferative effects are estrogen dependent in ER (estrogen receptor)-positive MCF-7 cells, being more pronounced in estrogen-containing media and in the presence of exogenous 17-beta estradiol. Curcumin inhibits the expression of ER downstream genes including pS2 and TGF-beta (transforming growth factor) in ER-positive MCF-7 cells, and this inhibition is also dependent on the presence of estrogen. Curcumin also decreases ERE (estrogen responsive element)-CAT activities induced by 17-beta estradiol. In addition, we demonstrate that curcumin exerts strong anti-invasive effects in vitro that are not estrogen dependent in the ER-negative MDA-MB-231 breast cancer cells. These anti-invasive effects appear to be mediated through the downregulation of MMP-2 (matrix metalloproteinase) and the upregulation of TIMP-1 (tissue inhibitor of metalloproteinase), 2 common effector molecules that have been implicated in regulating tumor cell invasion. Our study also demonstrates that curcumin inhibits the transcript levels of 2 major angiogenesis factors VEGF (vascular endothelial growth factor) and b-FGF (basic fibroblast growth factor) mainly in ER-negative MDA-MB-231 cells

Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer.

Sharma RA, McLelland HR, Hill KA, et al.

Clin Cancer Res. 2001 Jul; 7(7):1894-900.

Curcuma spp. extracts, particularly the dietary polyphenol curcumin, prevent colon cancer in rodents. In view of the sparse information on the pharmacodynamics and pharmacokinetics of curcumin in humans, a dose-escalation pilot study of a novel standardized Curcuma extract in proprietary capsule form was performed at doses between 440 and 2200 mg/day, containing 36-180 mg of curcumin. Fifteen patients with advanced colorectal cancer refractory to standard chemotherapies received Curcuma extract daily for up to 4 months. Activity of glutathione S-transferase and levels of a DNA adduct (M(1)G) formed by malondialdehyde, a product of lipid peroxidation and prostaglandin biosynthesis, were measured in patients' blood cells. Oral Curcuma extract was well tolerated, and dose-limiting toxicity was not observed. Neither curcumin nor its metabolites were detected in blood or urine, but curcumin was recovered from feces. Curcumin sulfate was identified in the feces of one patient. Ingestion of 440 mg of Curcuma extract for 29 days was accompanied by a 59% decrease in lymphocytic glutathione S-transferase activity. At higher dose levels, this effect was not observed. Leukocytic M(1)G levels were constant within each patient and unaffected by treatment. Radiologically stable disease was demonstrated in five patients for 2-4 months of treatment. The results suggest that (a) Curcuma extract can be administered safely to patients at doses of up to 2.2 g daily, equivalent to 180 mg of curcumin; (b) curcumin has low oral bioavailability in humans and may undergo intestinal metabolism; and (c) larger clinical trials of Curcuma extract are merited

The relationship between cyclooxygenase-2 expression and colorectal cancer 1.

Sheehan KM, Sheahan K, O'Donoghue DP, et al.

JAMA. 1999 Oct 6; 282(13):1254-7.

CONTEXT: Epidemiological studies have implicated the inducible form of cyclooxygenase (COX-2) in the pathogenesis of colorectal cancer; however, its role is not fully understood. OBJECTIVE: To examine the relationship between the expression of COX-2 in human colorectal cancer and patient survival. DESIGN: Patients diagnosed as having colorectal cancer were evaluated and followed up for up to 9.4 years (median follow-up, 2.7 years). Tumor sections were stained for COX-2 using a rabbit polyclonal antibody raised against human COX-2. The extent of COX-2 staining was graded by 2 observers blinded to outcome. Preabsorption of the anti-COX-2 antibody with a COX-2 peptide abolished the staining, demonstrating the specificity of the assay. SETTING: Gastrointestinal unit of a large general teaching hospital in Dublin, Ireland. PARTICIPANTS: Seventy-six patients (median age, 66.5 years) with colorectal cancer (Dukes tumor stage A, n = 9; Dukes B, n = 30; Dukes C, n = 25; Dukes D, n = 12) whose diagnosis was made between 1988 and 1991. Fourteen normal colon biopsies were stained for COX-2 as controls. MAIN OUTCOME MEASURES: Survival in years following diagnosis compared by extent of COX-2 epithelial staining (grade 1, <1%; grade 2, 1%-19%; grade 3, 20%-49%; grade 4, > or = 50%), Dukes stage, tumor size, and lymph mode metastasis. RESULTS: COX-2 was found in tumor epithelial cells, inflammatory cells, vascular endothelium, and/or fibroblasts. The extent of epithelial staining was heterogeneous, varying markedly among different tumors. Normal tissue adjacent to the tumors also stained weakly for COX-2. No COX-2 was detected in control tissue samples. The Kaplan-Meier survival estimate was 68% in patients who had grade 1 tumor epithelial staining compared with 35% in those with higher grades combined (log-rank chi2 = 5.7; P = .02). Greater expression of COX-2 correlated with more advanced Dukes stage (Kendall tau-b, 0.22; P = .03) and larger tumor size (Kendall tau-b, 0.21; P = .02) and was particularly evident in tumors with lymph node involvement (Kendall tau-b, 0.26; P = .02). CONCLUSIONS: Our data indicate that COX-2 expression in colorectal cancer may be related to survival. These data add to the growing epidemiological and experimental evidence that COX-2 may play a role in colorectal tumorigenesis

Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2.

Sheng H, Shao J, Kirkland SC, et al.

J Clin Invest. 1997 May 1; 99(9):2254-9.

A considerable amount of evidence collected from several different experimental systems indicates that cyclooxygenase-2 (COX-2) may play a role in colorectal tumorigenesis. Large epidemiologic studies have shown a 40-50% reduction in mortality from colorectal cancer in persons taking aspirin or other nonsteroidal antiinflammatory drugs on a regular basis. One property shared by all of these drugs is their ability to inhibit COX, a key enzyme in the conversion of arachidonic acid to prostaglandins. Two isoforms of COX have been characterized, COX-1 and COX-2. COX-2 is expressed at high levels in intestinal tumors in humans and rodents. In this study, we selected two transformed human colon cancer cell lines for studies on the role of COX-2 in intestinal tumorigenesis. We evaluated HCA-7 cells which express high levels of COX-2 protein constitutively and HCT-116 cells which lack COX-2 protein. Treatment of nude mice implanted with HCA-7 cells with a selective COX-2 inhibitor (SC-58125), reduced tumor formation by 85-90%. SC-58125 also inhibited colony formation of cultured HCA-7 cells. Conversely, SC-58125 had no effect on HCT-116 implants in nude mice or colony formation in culture. Here we provide evidence that there may be a direct link between inhibition of intestinal cancer growth and selective inhibition of the COX-2 pathway

Global and regional estimates of cancer mortality and incidence by site: II. Results for the global burden of disease 2000.

Shibuya K, Mathers CD, Boschi-Pinto C, et al.

BMC Cancer. 2002 Dec 26; 2(1):37.

BACKGROUND: Mortality estimates alone are not sufficient to understand the true magnitude of cancer burden. We present the detailed estimates of mortality and incidence by site as the basis for the future estimation of cancer burden for the Global Burden of Disease 2000 study. METHODS: Age- and sex- specific mortality envelope for all malignancies by region was derived from the analysis of country life-tables and cause of death. We estimated the site-specific cancer mortality distributions from vital records and cancer survival model. The regional cancer mortality by site is estimated by disaggregating the regional cancer mortality envelope based on the mortality distribution. Estimated incidence-to-mortality rate ratios were used to back calculate the final cancer incidence estimates by site. RESULTS: In 2000, cancer accounted for over 7 million deaths (13% of total mortality) and there were more than 10 million new cancer cases world wide in 2000. More than 60% of cancer deaths and approximately half of new cases occurred in developing regions. Lung cancer was the most common cancers in the world, followed by cancers of stomach, liver, colon and rectum, and breast. There was a significant variations in the distribution of site-specific cancer mortality and incidence by region. CONCLUSIONS: Despite a regional variation, the most common cancers are potentially preventable. Cancer burden estimation by taking into account both mortality and morbidity is an essential step to set research priorities and policy formulation. Also it can used for setting priorities when combined with data on costs of interventions against cancers

Enhancement of wound healing by curcumin in animals.

Sidhu GS, Singh AK, Thaloor D, et al.

Wound Repair Regen. 1998 Mar; 6(2):167-77.

Tissue repair and wound healing are complex processes that involve inflammation, granulation, and remodeling of the tissue. In this study, we evaluated the in vivo effects of curcumin (difeurloylmethane), a natural product obtained from the rhizomes of Curcuma longa on wound healing in rats and guinea pigs. We observed faster wound closure of punch wounds in curcumin-treated animals in comparison with untreated controls. Biopsies of the wound showed reepithelialization of the epidermis and increased migration of various cells including myofibroblasts, fibroblasts, and macrophages in the wound bed. Multiple areas within the dermis showed extensive neovascularization, and Masson's Trichrome staining showed greater collagen deposition in curcumin-treated wounds. Immunohistochemical localization of transforming growth factor-beta1 showed an increase in curcumin-treated wounds as compared with untreated wounds. In situ hybridization and polymerase chain reaction analysis also showed an increase in the mRNA transcripts of transforming growth factor-beta1 and fibronectin in curcumin-treated wounds. Because transforming growth factor-beta1 is known to enhance wound healing, it may be possible that transforming growth factor-beta1 plays an important role in the enhancement of wound healing by curcumin

Practice parameters for detection of colorectal neoplasms. The Standards Committee, The American Society of Colon and Rectal Surgeons.

Simmang CL, Senatore P, Lowry A, et al.

Dis Colon Rectum. 1999 Sep; 42(9):1123-9.

The importance of the ratio of omega-6/omega-3 essential fatty acids.

Simopoulos AP.

Biomed Pharmacother. 2002 Oct; 56(8):365-79.

Several sources of information suggest that human beings evolved on a diet with a ratio of omega-6 to omega-3 essential fatty acids (EFA) of approximately 1 whereas in Western diets the ratio is 15/1-16.7/1. Western diets are deficient in omega-3 fatty acids, and have excessive amounts of omega-6 fatty acids compared with the diet on which human beings evolved and their genetic patterns were established. Excessive amounts of omega-6 polyunsaturated fatty acids (PUFA) and a very high omega-6/omega-3 ratio, as is found in today's Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a low omega-6/omega-3 ratio) exert suppressive effects. In the secondary prevention of cardiovascular disease, a ratio of 4/1 was associated with a 70% decrease in total mortality. A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 PUFA had no effect. The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2-3/1 suppressed inflammation in patients with rheumatoid arthritis, and a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had adverse consequences. These studies indicate that the optimal ratio may vary with the disease under consideration. This is consistent with the fact that chronic diseases are multigenic and multifactorial. Therefore, it is quite possible that the therapeutic dose of omega-3 fatty acids will depend on the degree of severity of disease resulting from the genetic predisposition. A lower ratio of omega-6/omega-3 fatty acids is more desirable in reducing the risk of many of the chronic diseases of high prevalence in Western societies, as well as in the developing countries, that are being exported to the rest of the world

Structure of curcumin in complex with lipoxygenase and its significance in cancer.

Skrzypczak-Jankun E, Zhou K, McCabe NP, et al.

Int J Mol Med. 2003 Jul; 12(1):17-24.

Scientific research provides documented evidence that fatty acid metabolites have profound impact on carcinogenesis. Intervention into dioxygenase pathways might therefore effect development, metastasis and progression of many types of cancers. This work delivers the first 3D structural data and explains how curcumin interacts with the fatty acid metabolizing enzyme, soybean lipoxygenase. Curcumin binds to lipoxygenase in a non-competitive manner. Trapped in that complex, it undergoes photodegradation in the X-rays, but utilizes enzyme catalytic ability to form the peroxy complex Enz-Fe-O-O-R as 4-hydroperoxy-2-methoxy-phenol, that later transforms into 2-methoxycyclohexa-2,5-diene-1,4-dione. Our observations about this radiation and time-dependent inhibition add new information to the role that curcumin might play in cancer prevention and treatment

Effect of high fat consumption on cell proliferation activity of colorectal mucosa and on soluble faecal bile acids.

Stadler J, Stern HS, Yeung KS, et al.

Gut. 1988 Oct; 29(10):1326-31.

To assess the effect of fat consumption on the proliferation of the rectal mucosa, 30 normal volunteers (22 to 71 years) were randomly allocated to three groups: (a) basal low fat diet containing 30 g of fat per day; (b) the basal diet with doses of 30 g corn oil taken with each of the three meals: 120 g fat/day; (c) the basal diet with one dose of 90 g corn oil after the last meal: 120 g fat/day. Rectal biopsies were taken 15 cm from the anal verge after five days on the diets and mucosal cell proliferation was measured by labelling index (LI). The LI was significantly (p less than 0.01) higher in group (c) (9.2) than in group (a) (5.9), with group (b) intermediate (6.8). In multiple stepwise regression analysis, the data were best fitted with age and the variable indicating fat consumed as a bolus as predictors of LI (r2 = 0.39, p less than 0.001). In separate analyses the regression coefficient with age in the fat bolus group was 0.23, p less than 0.001. There was some tendency towards lower bile acids in the faecal water in group (a) than in groups (b) and (c) following the diets and between the bile acids and LI (for lithocholic acid r = 0.48, p = 0.01). These data show that dietary fat given as a bolus can lead to an increase in the proliferation of human colonic cells, possibly as a consequence of raised levels of cytotoxic acidic lipids in the faecal stream

Factors influencing the natural history of colorectal liver metastases.

Stangl R, Altendorf-Hofmann A, Charnley RM, et al.

Lancet. 1994 Jun 4; 343(8910):1405-10.

Palliative treatment of unresectable colorectal liver metastases is common and often justified with reference to historical data on the natural history of the disease. However, in view of the improved diagnostic accuracy of modern imaging techniques, these previously published series do not provide sufficient guidance to judge the prognostic efficacy of palliative treatment. In the late 1970s we started prospectively to collect data on consecutive patients with colorectal liver metastases according to a standard protocol. We now present data derived from this series on factors that may affect outcome in untreated patients. Between January, 1980, and December, 1990, 1099 consecutive patients were recorded, of whom 566 (51.5%) received no treatment for their hepatic tumour. Excluding 34 early deaths and 48 patients with a second malignant tumour, 484 patients provided the basis for analysis. All patients were followed up to July 1, 1993, or death. At the closing date of the study only 1 untreated patient was still alive. The impact of various factors on survival was analysed by univariate and multivariate analyses. Six independent determinants of survival were identified in the following order: percentage liver volume replaced by tumour (LVRT), grade of malignancy of the primary tumour, presence of extrahepatic disease, mesenteric lymph-node involvement, serum carcino-embryonic antigen, and age. The subsequent combination of the independently significant factors, separately for patients with up to or more than 25% LVRT, yielded a prognostic tree that displayed median survival times of various subgroups of 3.8 to 21.3 months. These findings provide a framework to estimate the survival expectancy of untreated patients, thereby allowing improved assessment of the prognostic significance of palliative therapeutic approaches

Calcium reduces the increased fecal 1,2-sn-diacylglycerol content in intestinal bypass patients: a possible mechanism for altering colonic hyperproliferation.

Steinbach G, Morotomi M, Nomoto K, et al.

Cancer Res. 1994 Mar 1; 54(5):1216-9.

Diacylglycerol (DAG) is a second messenger for protein kinase C, an enzyme with a key role in cellular signal transduction and growth control. In previous studies, it was demonstrated that DAG is produced by intestinal microflora. Bacterial DAG production is increased by bile acids and phospholipids, both of which may be precipitated by calcium. We have demonstrated that fecal total lipids, bile acids, and rectal epithelial proliferation are increased in intestinal bypass (IB) patients. Calcium was shown to alter fecal lipid composition and to reduce cell proliferation. In the present study, fecal DAG content and 14C-labeled DAG, 14C-phosphatidylcholine, and 14C-phosphatidylinositol metabolism were measured in 24-h stool collections in 15 stable IB patients before and after 3-month therapy with oral elemental calcium, 2.4 or 3.6 g/day. Fecal DAG concentration and output in IB patients were > 25- and > 200-fold greater than in normal controls. Oral calcium markedly reduced fecal DAG concentration and output and increased DAG, phosphatidylcholine, and phosphatidylinositol metabolism without enhancing DAG production. We conclude that fecal DAG content is markedly elevated post-IB and that calcium supplementation in these patients reduces fecal DAG and accelerates bacterial metabolism of DAG and its precursors. In separate studies, we have found that calcium supplementation also decreases rectal hyperproliferation in IB patients. Taken together, these findings suggest that a high luminal level of DAG enhances colonic cell proliferation and that calcium reduces cell proliferation in part by decreasing the level of DAG

Cancer risk in relation to fat and energy intake among Hawaii Japanese: a prospective study.

Stemmermann GN, Nomura AM, Heilbrun LK.

Princess Takamatsu Symp. 1985; 16:265-74.

This study assesses the impact of fat and energy consumption upon cancer risk in a prospective study of 8,006 Japanese men, who have developed 885 incidence cancers since initial examinations were completed between 1965 and 1968. Energy intake was not related to any incidence cancer. The mean total fat intake was unrelated to the risk of developing cancers in the stomach (n = 130), lung (n = 145), urinary bladder (n = 51), pancreas (n = 25), prostate (n = 141), liver (n = 22). There was a weak inverse association between mean fat intake and colon cancer. There was a statistically significant inverse relation between mean daily fat intake and all other cancers (n = 118). There was a weakly positive association between fat intake and rectal cancer (n = 71). When assessed on the basis of quartiles of fat intake, there was a statistically significant negative association with colon cancer risk (p = 0.03); and weaker negative trends for lung cancer (p = 0.076) and all other cancers (0.076). These findings are in essential agreement with the results of a 10-year mortality study of the cohort. The fat intake of men who have developed cancer is substantially lower than that of men who have developed coronary heart disease. These findings cast doubt upon the importance of fat intake as a risk factor for cancer at sites other than the rectum

Functional food ingredients against colorectal cancer. An example project integrating functional genomics, nutrition and health.

Stierum R, Burgemeister R, van Helvoort A, et al.

Nutr Metab Cardiovasc Dis. 2001 Aug; 11(4 Suppl):94-8.

Functional Food Ingredients Against Colorectal Cancer is one of the first European Union funded Research Projects at the cross-road of functional genomics [comprising transcriptomics, the measurement of the expression of all messengers RNA (mRNAs) and proteomics, the measurement of expression/state of all proteins], nutrition and human health. The goal of Functional Food Ingredients Against Colorectal Cancer is to develop a colon epithelial cell line-based screening assay for nutrients with presumed anti-colorectal carcinogenic properties. Genes involved in colon carcinogenesis are identified at the RNA and protein level, using a variety of methods (subtractive hybridisation, DNA microarray, proteomics) in combination with models for colorectal cancer development (human biopsies, rat model for colorectal carcinogenesis, colorectal cancer epithelial cell lines). Secondly, colorectal cancer epithelial cell lines are selected, in terms of their capacity to undergo gene/protein expression changes representing different phases in the colorectal carcinogenesis. Thirdly, these cell lines are used to determine the effects of nutrients with presumed anti-carcinogenic properties (e.g. resveratrol, flavonoids) on functional genomics-derived endpoints. Once validated against the effects of these nutrients in in vivo animal models and classical biomarkers for colorectal carcinogenesis, these cell line models combined with functional genomics represent useful tools to study colorectal carcinogenesis and screen for nutrients with anti-carcinogenic properties

Intraoperative radiofrequency ablation using a 3D navigation tool for treatment of colorectal liver metastases.

Stippel DL, Bohm S, Beckurts KT, et al.

Onkologie. 2002 Aug; 25(4):346-50.

BACKGROUND: Resection as the only potential cure for colorectal liver metastasis is limited by the size and the intrahepatic localization of lesions. Radiofrequency ablation (RFA) may extend the limitations of surgery. PATIENTS AND METHODS: 23 consecutive patients suffering from a total of 128 colorectal liver metastases were treated by resection and intraoperative RFA. All of these patients were irresectable by standard surgery due to volume and distribution of the lesions. 17 patients were treated by chemotherapy before RFA, with only 1 patient showing partial regression of liver metastases. In 12 lesions a new 3D navigation tool was used, that allows a virtual overlay of the RFA probe in real-time. RESULTS: 60 metastases were resected, 68 metastases were treated by RFA. There was no mortality, and complications occurred in 4 patients only (1??temporary encephalopathy, 3x cholangitis). Local tumor control according to CT scan was achieved by RFA in 93% of lesions up to 30 mm diameter (n = 45) and in 44% of lesions larger than 30 mm (n = 23). All ablations using the navigation tool were successful. After a mean follow-up of 8 +/- 5 months 12 patients are free of disease, 8 patients have either recurrent or new metastases, and 3 patients died of progressive disease. The estimated median survival time is 18 months (95% confidence interval 13-22 months). CONCLUSIONS: Intraoperative RFA of colorectal liver metastases in combination with hepatic resection is safe. Up to a lesion size of 30 mm a reliable treatment with RFA is possible. The navigation aid increases the reproducibility of the procedure

Angiogenesis and antiangiogenic therapy of colon cancer liver metastasis.

Stoeltzing O, Liu W, Reinmuth N, et al.

Ann Surg Oncol. 2003 Aug; 10(7):722-33.

The fact that tumor growth and metastatic spread relies on angiogenesis has been widely proven and accepted. The understanding of cancer biology and metastasis formation has led to the development of new therapeutic approaches that target tumor biology. The survival and establishment of metastatic lesions depend on a shift in the normal balance of proangiogenic and antiangiogenic factors that favor angiogenesis. Colorectal cancer is one of the leading cancer deaths worldwide. Angiogenesis has been associated with colon cancer progression and metastatic spread, thereby significantly affecting patient survival. New experimental approaches that inhibit angiogenic processes have demonstrated promising antineoplastic effects on metastatic colorectal cancer and are partially being investigated in clinical trials. This review focuses on angiogenesis in colorectal cancer metastasis formation as a target for antiangiogenic therapy, describing the experience from experimental studies and current clinical trials

Tea consumption and the reduced risk of colon cancer -- results from a national prospective cohort study.

Su LJ, Arab L.

Public Health Nutr. 2002 Jun; 5(3):419-25.

OBJECTIVE: This study examines the relationship between tea consumption and colon cancer risk in the US population. DESIGN: Data from the NHANES I Epidemiologic Follow-up study (NHEFS) were used to examine the hypothesis. Cox proportional hazard models were used to examine the hypothesis of a protective effect of frequent tea consumption on colon cancer occurrence. SETTING: Due to differences in the precision of the exposure data, we analysed two cohort periods based on the NHEFS. Cohort I was based on the survey conducted at the NHEFS baseline and Cohort II began at the first follow-up. SUBJECTS: After excluding non-incidence cases and cases lost to follow-ups, there were 2359 tea users and 6498 non-tea users at baseline and 7656 tea users and 4514 non-tea users at the first follow-up. RESULTS:: After adjusting for confounders, the relative risks of colon cancer are 0.57 (95% confidence interval (CI) 0.42, 0.78) and 0.59 (95% 1.00) for subjects who consumed 1.5 cups per day, respectively, compared with non-tea users in Cohort II. Although more women consumed tea and the mean intake was higher, the preventive effect of tea consumption on colon cancer was found predominantly in men. The relative risks of colon cancer are 0.41 (95% 0.66) for men who consumed 1.5 cups day-1 of tea consumption (P-value for trend <0.01). No significant results were found in Cohort I. CONCLUSIONS: This study suggests an inverse association between colon cancer risk and habitual tea consumption

Increase by deoxycholic acid of the colonic nuclear damage induced by known carcinogens in C57BL/6J mice.

Suzuki K, Bruce WR.

J Natl Cancer Inst. 1986 Jun; 76(6):1129-32.

Intrarectal exposure of the colon epithelium of the C57BL/6J female mouse to deoxycholic acid [(DCA) CAS: 83-44-3] markedly increased its sensitivity to orally administered 1,2-dimethylhydrazine [(DMH) CAS: 540-73-8]. While 4 mg DMH/kg body weight by itself increased the level of nuclear damage from a background level of 0.2-0.45 aberration per crypt, DMH when combined with DCA at a dose of 150 mg/kg increased the aberrations from 0.2 to 1.75 per crypt. This effect was observed over a wide range of DCA doses (20-300 mg/kg) and was evident when DMH was given up to 10 hours after the DCA. Similar results were observed with DCA in conjunction with benzo[a]pyrene (CAS: 50-32-8) and 2-amino-3,4-dimethylimidazo(4,5-f)quinoline (CAS: 77094-11-2), though in these cases the time at which the peak of nuclear aberrations occurred was somewhat later. No enhancement was seen with DCA and gamma-radiation. These results show that DCA can enhance the nucleotoxic effects of several carcinogens and suggest that DCA can act as a cocarcinogen. The enhancement may be due to the effect of the bile acid on proliferation of the colon epithelial cells or to its effect on the permeability of mucosal cells

Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer.

Takahashi Y, Tucker SL, Kitadai Y, et al.

Arch Surg. 1997 May; 132(5):541-6.

BACKGROUND: The value of these prognostic factors was compared with that of other clinicopathologic factors such as tumor grade, tumor stage, mucin production, vascular invasion, perineural invasion, and lymphatic invasion. OBJECTIVE: To determine whether the development of distant recurrence in patients with node-negative colon cancer could be predicted using vessel count and vascular endothelial growth factor (VEGF) expression. DESIGN: Paraffin-embedded colon cancers were immunostained for factor VIII, VEGF, basic fibroblast growth factor, and proliferating cell nuclear antigen; slides were reviewed for differentiation, mucin production, and the presence of vascular, lymphatic, and/or perineural invasion. SETTING: A large academic cancer referral center where 27 patients with node-negative colon cancer were operated on during 1988 and 1989. MAIN OUTCOME MEASURE: The development of and interval to recurrence. RESULTS: Eight patients developed liver, lung, or lymph node metastases at a median of 24 months. The median follow-up for patients without cancer recurrence was 60 months. The mean tumor vessel count for those patients who remained disease-free was significantly fewer than for those patients who suffered a recurrence (20 vs 33, respectively). By univariate analysis, 3 factors- perineural invasion, vessel count, and VEGF expression- were correlated with time to recurrence. By multivariate analysis, only vessel count was significantly related to differences in time to recurrence. Expression of VEGF correlated with vessel count. CONCLUSION: Vessel count and expression of VEGF may be useful for predicting distant recurrence in patients with node-negative colon cancer

[Detection of serum p53 antibodies in colorectal cancer patients and the clinical significance of postoperative monitoring].

Takeda A, Shimada H, Nakajima K, et al.

Gan To Kagaku Ryoho. 1999 Dec; 26(14):2189-94.

p53 protein overexpression was found to induce the production of antibodies in patient serum and, recently, the easy detection of serum antibodies has been made possible. The aim of this study is to determine the significance of serum p53 antibodies in patients with primary colorectal adenocarcinoma in comparison with their clinicopathological features, and the tumor marker sensitivities of carcinoembryonic antigen (CEA), carcinoma antigen 19-9 (CA19-9) and alpha-fetoprotein (AFP). Thirty-nine of 86 patients (45.3%) were positive for serum p53 antibodies. However, there was no relation with the cancer progression or clinicopathological findings. The sensitivities of CEA, CA19-9 and AFP were 36.0%, 38.4%, and 8.1% respectively, but there was no relation between serum p53 antibodies and these three markers. When the sensitivity of serum p53 antibodies and CEA was evaluated according to clinical stage, the presence of serum p53 antibodies was more significantly associated with stage 0, I and II colorectal cancer than was CEA. Thirty-three patients who showed preoperative positivity for serum p53 antibodies were followed by serial evaluation of circulating antibodies after resection. Negative conversions after resection were significantly higher in the "Cur A" group than in the "Cur B" or "Cur C" groups. Serum p53 antibodies appear to be a useful tumor marker independent of the other markers, especially in the early stage, and are expected to be useful in the development of a method of early diagnosis for mass screening, and as a postoperative monitoring marker for colorectal cancer

Cooperative inhibitory effects of antisense oligonucleotide of cell adhesion molecules and cimetidine on cancer cell adhesion.

Tang NH, Chen YL, Wang XQ, et al.

World J Gastroenterol. 2004 Jan; 10(1):62-6.

AIM: To explore the cooperative effects of antisense oligonucleotide (ASON) of cell adhesion molecules and cimetidine on the expression of E-selectin and ICAM-1 in endothelial cells and their adhesion to tumor cells.METHODS: After treatment of endothelial cells with ASON and/or cimetidine and induction with TNF-alpha, the protein and mRNA changes of E-selectin and ICAM-1 in endothelial cells were examined by flow cytometry and RT-PCR, respectively. The adhesion rates of endothelial cells to tumor cells were measured by cell adhesion experiment. RESULTS: In comparison with TNF-alpha inducing group, lipo-ASON and lipo-ASON/cimetidine could significantly decrease the protein and mRNA levels of E-selectin and ICAM-1 in endothelial cells, and lipo-ASON/cimetidine had most significant inhibitory effect on E-selectin expression (from 36.37+/-1.56% to 14.23+/-1.07%, P<0.001). Meanwhile, cimetidine alone could inhibit the expression of E-selectin(36.37+/-1.56% vs 27.2+/-1.31%, P<0.001), but not ICAM-1 (69.34+/-2.50% vs 68.07+/-2.10%,P>0.05) and the two kinds of mRNA, either. Compared with TNF-alpha inducing group, the rate of adhesion was markedly decreased in lipo-E-selectin ASON and lipo-E-selectin ASON/cimetidine treated groups(P<0.05), and lipo-E-selectin ASON/cimetidine worked better than lipo-E-selectin ASON alone except for HepG2/ECV304 group (P<0.05). However, the decrease of adhesion was not significant in lipo-ICAM-1 ASON and lipo-ICAM-1 ASON/cimetidine treated groups except for HepG2/ECV304 group (P>0.05). CONCLUSION: These data demonstrate that ASON in combination with cimetidine in vitro can significantly reduce the adhesion between endothelial cells and hepatic or colorectal cancer cells, which is stronger than ASON or cimetidine alone. This study provides some useful proofs for gene therapy of antiadhesion

The antioxidant role of selenium and seleno-compounds.

Tapiero H, Townsend DM, Tew KD.

Biomed Pharmacother. 2003 May; 57(3-4):134-44.

Selenium (Se) is an essential trace element for animals and humans that is obtained from dietary sources including cereals, grains and vegetables. The Se content of plants varies considerably according to its concentration in soil. Plants convert Se mainly into Se-methionine (Se-Met) and incorporate it into protein in place of methionine (Met). Selenocystine (Se-Cys), methyl-Se-Cys and gamma-glutamyl-Se-methyl-Cys are not significantly incorporated into plant protein and are at relatively low levels irrespective of soil Se content. Higher animals are unable to synthesize Se-Met and only Se-Cys was detected in rats supplemented with Se as selenite. Renal regulation is the mode by which whole body Se is controlled. Se is concentrated in hair and nail and it occurs almost exclusively in organic compounds. The potentiating effect of Se deficiency on lipid peroxidation is enhanced in some tissues by concurrent deficiency of copper or manganese. In the in vitro system, the chemical form of Se is an important factor in eliciting cellular responses. Although the cytotoxic mechanisms of selenite and other redoxing Se compounds are still unclear, it has been suggested that they derive from their ability to catalyze the oxidation of thiols and to produce superoxide simultaneously. Selenite-induced cytotoxicity and apoptosis in human carcinoma cells can be inhibited with copper (CuSO(4)) as an antioxidant. High doses of selenite result in induction of 8-hydroxydeoxyguanosine (8-OHdG) in mouse skin cell DNA and in primary human keratinocytes. It may cause DNA fragmentation and decreased DNA synthesis, cell growth inhibition, DNA synthesis, blockade of the cell cycle at the S/G(2)-M phase and cell death by necrosis. In contrast, in cells treated with methylselenocyanate or Se methylselenocysteine, the cell cycle progression was blocked at the G(1) phase and cell death was predominantly induced by apoptosis

Pilot study--cimetidine enhances lymphocyte infiltration of human colorectal carcinoma: results of a small randomized control trial.

Tavani A, Fioretti F, Franceschi S, et al.

Cancer. 1998 Jun 1; 82(11):2296-7.

Dietary calcium and vitamin D intake and risk of colorectal cancer: a prospective cohort study in women.

Terry P, Baron JA, Bergkvist L, et al.

Nutr Cancer. 2002; 43(1):39-46.

Although laboratory data and a few adenoma prevention trials suggest that calcium supplementation may reduce the risk of colorectal neoplasia, the results of observational studies of calcium intake and colorectal cancer risk are contradictory. However, few studies have examined the association among women or effects in specific colon subsites. Women with colorectal cancer diagnosed through 31 December 2000 were identified by linkage to regional cancer registries. During an average 11.3 yr of follow-up of 61,463 women, we observed 572 incident cases of colorectal cancer. Using data obtained from a 67-item food frequency questionnaire and Cox proportional hazards models to estimate rate ratios and 95% confidence intervals, we found an inverse association between dietary calcium intake and colorectal cancer risk. Women with the highest calcium intake (median 914 mg/day) had a reduced risk of colorectal cancer (rate ratio = 0.72, 95% confidence interval = 0.056-0.93, P for trend = 0.02) compared with women with the lowest intake (median 486 mg/day). Furthermore, our results suggest that the inverse association may be strongest in relation to distal cancers and among older women. The association with dairy products was less clear, suggesting that calcium intake per se is more important than specific calcium sources. Vitamin D intake was not clearly associated with risk. In sum, our data suggest that high calcium intake may lower colorectal cancer risk

Omega-3 fatty acid supplementation reduces tumor growth and vascular endothelial growth factor expression in a model of progressive non-metastasizing malignancy.

Tevar R, Jho DH, Babcock T, et al.

JPEN J Parenter Enteral Nutr. 2002 Sep; 26(5):285-9.

BACKGROUND: Omega-3 fatty acids, the principal component of fish oil, have been demonstrated to have antiinflammatory properties. The role of eicosapentaenoic acid (EPA) supplementation for cancer patients is currently under investigation; however, the mechanisms of EPA activity have not been defined. The purpose of this study was to characterize tumor-specific and treatment-specific effects of supplemental dietary EPA in an animal model of progressive malignancy. METHODS: Fischer 344 rats (200-250 g) underwent flank implantation of the methycholanthrene (MCA)-induced fibrosarcoma on day 0. Rats were randomly divided into 3 treatment groups on day 13: EPA (1 mL, 5.0 g/kg per day) + 10 IU vitamin E; corn oil (1 mL) + 10 IU vitamin E, and saline (1 mL) + 10 IU vitamin E (vitamin E was used to prevent fatty acid oxidation). On day 14, gavage feeding was started and was continued through day 28. The animals were killed on day 29, and the tumors were removed. The tumors were weighed and divided by the tumor-free carcass weight to obtain percentage of tumor volume, and the livers were flash frozen. Vascular endothelial growth factor-alpha (VEGF-alpha) and cyclo-oxygenase 2 (COX-2) mRNA were measured by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: EPA rats had significant reductions in tumor volume compared with isocaloric corn oil and control saline animals (25%, p < .01 and 33%, p < .01, respectively). Rats receiving EPA demonstrated decreased VEGF-alpha mRNA levels (0.023 +/- 0 0.001) compared with those receiving corn oil (0.129 +/- 0.047) or saline (0.150 +/- 0.026; p < .05). CONCLUSIONS: These data demonstrate that EPA supplementation inhibits tumor growth, potentially through alterations in the expression of the pro-angiogenic VEGF-alpha. The mechanism(s) of EPA as an inhibitor of tumor-related angiogenic growth factors may be associated with COX-2 enzyme fatty acid metabolism and merits further study

Population-based surveillance by colonoscopy: effect on the incidence of colorectal cancer. Telemark Polyp Study I.

Thiis-Evensen E, Hoff GS, Sauar J, et al.

Scand J Gastroenterol. 1999 Apr; 34(4):414-20.

BACKGROUND: Most cases of colorectal cancer (CRC) develop from adenomas. Polypectomy is believed to reduce the incidence of CRC, but this effect has never been explored in prospective controlled studies. The aim of the present study was to evaluate the effect of polypectomy on colorectal cancer incidence in a population-based screening program. METHODS: In 1983, 400 men and women aged 50-59 years were randomly drawn from the population registry of Telemark, Norway. They were offered a flexible sigmoidoscopy and, if polyps were found, a full colonoscopy with polypectomy and follow-up colonoscopies in 1985 and 1989. A control group of 399 individuals was drawn from the same registry. In 1996 both groups (age, 63-72 years) were invited to have a colonoscopic examination. Hospital files and the files of The Norwegian Cancer Registry were searched to register any cases of CRC in the period 1983-96. RESULTS: At screening endoscopy 324 (81%) individuals attended in 1983 and 451 (71%) in 1996. From 1983 to 1996, altogether 10 individuals in the control group and 2 in the screening group were registered to have developed CRC (relative risk, 0.2; 95% confidence interval (CI), 0.03-0.95; P = 0.02). A higher overall mortality was observed in the screening group, with 55 (14%) deaths, compared with 35 (9%) in the control group (relative risk, 1.57; 95% CI, 1.03-2.4; P = 0.03). CONCLUSION: Endoscopic screening examination with polypectomy and follow-up was shown to reduce the incidence of CRC in a Norwegian normal population. The possible effect of screening on overall mortality should be addressed in larger studies

Colorectal cancer. Radiologic staging.

Thoeni RF.

Radiol Clin North Am. 1997 Mar; 35(2):457-85.

The role of conventional CT scan and conventional MR imaging in assessing patients with colorectal tumors is now well established. Because both techniques have an unacceptably low accuracy for identifying the early stages of primary colorectal cancers (T1, T2N0 or N1 and early T3N0 or N1, or Dukes stage A, B1 and 2, and C1), their routine use for preoperative staging is not recommended. This low staging accuracy is related to the fact that neither method can assess the depth of tumor infiltration within the bowel wall and both have difficulty in diagnosing malignant adenopathy. These distinctions are necessary in order to determine correctly patient prognosis and tumor resectability. If the various publications on CT scan and MR imaging staging of primary colon tumors are summarized, a mean overall accuracy of approximately 70% can be established. The sensitivity for lymph node detection of malignant lymphadenopathy is only about 45%. The sensitivity for detection of positive lymph nodes is better for rectal tumors because any adenopathy in the perirectal area can be considered malignant because benign adenopathy is not seen in this area. For the early stages of colon cancer or recurrent tumor at the anastomotic site, endoscopic ultrasound or TRUS is the method of choice. Both TRUS and MR imaging with endorectal coils can demonstrate the various layers of the rectal wall, but the ultrasonographic examination can be performed at lower cost and is less time-consuming. Despite these limitations CT scan and MR imaging are useful for assessing patients suspected of having extensive disease, including invasion of fat or neighboring organs or metastatic spread to distant sites including, liver, adrenals, lung, and so forth. CT scan and MR imaging are also helpful in the following ways: in determining whether a patient will benefit from preoperative radiation or whether a patient with rectal cancer can undergo a sphincter-saving procedure; for designing radiation ports; and for detecting complications related to the neoplasm, such as perforation with abscess formation or preobstructive ischemia in patients with complete obstruction by tumor. In these cases, management often is based on CT scan and MR imaging findings and cross-sectional follow-up studies can establish the success of treatment. CT scan and MR imaging have a premier role in the detection of recurrent colorectal cancer. CT scan and MR imaging are superior to colonoscopy for diagnosing extrinsic mass-like tumor recurrences and they are the only methods by which patients with total AP resection can be fully evaluated. The overall accuracy of CT scan and MR imaging for detecting recurrent colorectal tumors ranges from 90% to 95%. Following AP resection, CT scan cannot reliably determine whether a soft tissue density in the surgical bed represents recurrent tumor, and it is important to obtain CT scan baseline studies 4 months after surgery and to repeat this examination at 6-month intervals. Scar tissue, even if initially masslike, shrinks over time and after 1 year should be smaller and its margins more sharply defined. Any apparent increase in size of a mass or any demonstration of adenopathy must be considered an indication for biopsy. Recurrent tumors that do not extend to the pelvis or abdominal sidewalls or invade bone or nerves can be resected. Subtle tumor recurrence or tumor foci in small nodes can be detected by PET scan and immunoscintigraphy, but their future role in the diagnostic imaging of colorectal cancer patients depends on the results of ongoing studies. Helical CT scan has the advantages of fast volume scanning associated with optimal bolus delivery, absence of artifacts related to motion, absence of missed slices, and availability of reformations in multiple planes and three-dimensional reconstruction (virtual reality). The role of this technique in patients with colorectal neoplasms has not been defined. (ABSTRACT TRUNCATED)

Citrus pectin and oligofructose improve folate status and lower serum total homocysteine in rats.

Thoma C, Green TJ, Ferguson LR.

Int J Vitam Nutr Res. 2003 Nov; 73(6):403-9.

Low folate status leads to increased total homocysteine (tHcy) concentration, and this has been associated with an increased risk of several diseases. Many colonic bacteria are capable of synthesizing folate, and certain dietary fibers may enhance this effect. We assessed the ability of non-fermentable (cellulose) and fermentable (citrus pectin and oligofructose) fibers to improve folate status and lower tHcy in rats. Weanling Sprague-Dawley rats were fed a folate-deficient diet with 5% cellulose for four weeks. Rats were then randomly assigned to one of five folate-adequate (400 micrograms/kg diet) test diets for 24 days. Diets were as follows: Basal; Basal + Sulfa Drug (succinylsulfathiazole); Cellulose; Citrus Pectin; and Oligofructose. High-fiber diets were formulated by diluting the basal diet such that the final diets contained 10% of the added fiber. Twenty-one days later, 3H-p-aminobenzoic acid was injected into the cecum, and rats were terminated three days later. Rats receiving the Citrus Pectin diet had significantly higher plasma (p = 0.011), erythrocyte (p = 0.035), and colonic tissue folate concentrations (p = 0.013) and lower tHcy (p = 0.003) than rats given the Cellulose diet. Rats receiving the Oligofructose had significantly higher plasma folate (p < 0.001) and lower tHcy (p = 0.032) concentrations than rats receiving the Cellulose diet. 3H-folate was detected in the livers of all rats except those receiving Sulfa Drug. Our study indicates that Citrus Pectin and Oligofructose, but not Cellulose, can significantly increase indices of folate status in rats and lower tHcy. It also confirms the ability of the large bowel to absorb folate

FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.

Tournigand C, Andre T, Achille E, et al.

J Clin Oncol. 2004 Jan 15; 22(2):229-37.

PURPOSE: In metastatic colorectal cancer, phase III studies have demonstrated the superiority of fluorouracil (FU) with leucovorin (LV) in combination with irinotecan or oxaliplatin over FU + LV alone. This phase III study investigated two sequences: folinic acid, FU, and irinotecan (FOLFIRI) followed by folinic acid, FU, and oxaliplatin (FOLFOX6; arm A), and FOLFOX6 followed by FOLFIRI (arm B). PATIENTS AND METHODS: Previously untreated patients with assessable disease were randomly assigned to receive a 2-hour infusion of l-LV 200 mg/m(2) or dl-LV 400 mg/m(2) followed by a FU bolus 400 mg/m(2) and 46-hour infusion 2,400 to 3,000 mg/m(2) every 46 hours every 2 weeks, either with irinotecan 180 mg/m(2) or with oxaliplatin 100 mg/m(2) as a 2-hour infusion on day 1. At progression, irinotecan was replaced by oxaliplatin (arm A), or oxaliplatin by irinotecan (arm B). RESULT: Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI (P =.99). Median second progression-free survival (PFS) was 14.2 months in arm A versus 10.9 in arm B (P =.64). In first-line therapy, FOLFIRI achieved 56% response rate (RR) and 8.5 months median PFS, versus FOLFOX6 which achieved 54% RR and 8.0 months median PFS (P =.26). Second-line FOLFIRI achieved 4% RR and 2.5 months median PFS, versus FOLFOX6 which achieved 15% RR and 4.2 months PFS. In first-line therapy, National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis, nausea/vomiting, and grade 2 alopecia were more frequent with FOLFIRI, and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6. CONCLUSION: Both sequences achieved a prolonged survival and similar efficacy. The toxicity profiles were different

Detection of proximal colorectal cancers through analysis of faecal DNA.

Traverso G, Shuber A, Olsson L, et al.

Lancet. 2002 Feb 2; 359(9304):403-4.

Detection of mutations in faecal DNA represents a promising, non-invasive approach for detecting colorectal cancers in average-risk populations. One of the first practical applications of this technology involves the examination of microsatellite markers in sporadic cancers with mismatch-repair deficiencies. Since such cancers nearly always occur in the proximal colon, this test might be useful as an adjunct to sigmoidoscopy, which detects only distal colorectal lesions. We report here the first in-depth analysis of faecal DNA from patients with proximal cancers to determine the feasibility, sensitivity, and specificity of this approach. Using a sensitive method for microsatellite mutation detection, we found that 18 of 46 cancers had microsatellite alterations and that identical mutations could be identified in the faecal DNA of 17 of these 18 cases

Micronutrients and the risk of colorectal adenomas.

Tseng M, Murray SC, Kupper LL, et al.

Am J Epidemiol. 1996 Dec 1; 144(11):1005-14.

Recent studies suggest that micronutrients, especially folate, calcium, iron, and antioxidant vitamins, affect the risk of colorectal neoplasia. The objective of this case-control study was to examine the association between these micronutrients and the risk of colorectal adenomas. The study was based on 236 cases with adenomatous polyps or cancer and 409 controls, all colonoscopy patients at University of North Carolina Hospitals between July 1988 and March 1991. After colonoscopy, subjects were interviewed using a semi-quantitative food frequency questionnaire, and average daily nutrient intakes were calculated. Sex-specific odds ratios relative to the lowest quartile of intake for each micronutrient were determined using unconditional logistic regression while adjusting for a number of potential confounders. In women, folate, iron, and vitamin C were inversely related to the risk of adenomas. Folate appeared to be most protective, with women in the highest quartile only 40% as likely to develop adenomas compared with women in the lowest (odds ratio = 0.39, 95% confidence interval 0.15-1.01). In men, greater vitamin E and calcium intakes were associated with reduced risk of adenomas, with vitamin E showing the strongest inverse association. Men in the highest vitamin E quartile had a risk of 0.35 (95% confidence interval 0.14-0.92) relative to those in the lowest. These study results support previous research findings that selected micronutrients protect against colorectal neoplasia

Cyclooxygenase regulates angiogenesis induced by colon cancer cells.

Tsujii M, Kawano S, Tsuji S, et al.

Cell. 1998 May 29; 93(5):705-16.

To explore the role of cyclooxygenase (COX) in endothelial cell migration and angiogenesis, we have used two in vitro model systems involving coculture of endothelial cells with colon carcinoma cells. COX-2-overexpressing cells produce prostaglandins, proangiogenic factors, and stimulate both endothelial migration and tube formation, while control cells have little activity. The effect is inhibited by antibodies to combinations of angiogenic factors, by NS-398 (a selective COX-2 inhibitor), and by aspirin. NS-398 does not inhibit production of angiogenic factors or angiogenesis induced by COX-2-negative cells. Treatment of endothelial cells with aspirin or a COX-1 antisense oligonucleotide inhibits COX-1 activity/expression and suppresses tube formation. Cyclooxygenase regulates colon carcinoma-induced angiogenesis by two mechanisms: COX-2 can modulate production of angiogenic factors by colon cancer cells, while COX-1 regulates angiogenesis in endothelial cells

Role of NK cell cytotoxic factor against fresh human tumors.

Uchida A, Fukata H.

Nat Immun. 1993 Jul; 12(4-5):267-78.

Blood lymphocytes of cancer patients lysed autologous, freshly isolated tumor cells. The autologous tumor-killing (ATK) activity is strongly associated with postoperative clinical course, indicating that ATK is a meaningful prognostic indicator and provides evidence for immunological control of tumor growth and metastasis. Large granular lymphocytes (LGL) with ATK activity released a soluble cytotoxic factor(s), termed LGL-CF (LGL-derived cytotoxic factor) during interaction with autologous tumor cells. The cytotoxic factor lysed autologous and allogeneic freshly isolated human tumor cells, while they were resistant to any of recombinant cytokines, including tumor necrosis factor (TNF), lymphotoxin (LT), interferon (IFN) alpha, IFN gamma, interleukin (IL)-1 alpha and IL-2. Biological activity of LGL-CF was not abrogated by monoclonal and polyclonal antibodies against these cytokines. LGL-CF also exhibited lysis of a variety of tumor cell lines, but not of nonmalignant cells. Actinomycin D augmented the lysis of LGL-CF. LGL-CF was stable at 56 degrees C, but was destroyed at 100 degrees C. Treatment of LGL-CF with trypsin or proteinase K reduced or abrogated the lytic effect, respectively, while it was resistant to papain, catalase, and superoxide dismutase. These results indicate that LGL produce a novel cytotoxic factor in response to autologous tumor cells that mediates lysis of fresh human tumor cells

Calcium or resistant starch does not affect colonic epithelial cell proliferation throughout the colon in adenoma patients: a randomized controlled trial.

van Gorkom BA, Karrenbeld A, van der ST, et al.

Nutr Cancer. 2002; 43(1):31-8.

Patients with a history of sporadic adenomas have increased epithelial cell proliferative activity, an intermediate risk marker for colorectal cancer. Reduction of proliferation by dietary intervention may reflect a decreased colorectal cancer risk. To evaluate whether calcium or resistant starch could reduce proliferative activity throughout the colon, we performed a randomized controlled trial in 111 sporadic adenoma patients. Patients received two placebos, 1 g of calcium + placebo, or 30 g of amylomaize (19 g of resistant starch) + placebo. After 2 mo, biopsies were collected from the cecum, transverse and sigmoid colon, and rectum during colonoscopy. Epithelial cell proliferation was determined by dividing the number of 5-bromo-2-deoxyuridine-labeled nuclei by the total number of nuclei x 100 (labeling index, LI). LI of luminal, mid, and basal compartments was determined. Twenty-five patients dropped out. In the remaining 86 patients (28 treated with placebo, 30 with calcium + placebo, and 28 with resistant starch + placebo), no difference was observed in total LI, the LI of the three compartments, or the crypt length in the four areas of the colorectum. Colonic epithelial cell proliferative activity throughout the colon of sporadic adenoma patients is not affected by supplementation with 1 g of calcium or 19 g of resistant starch

Genetic alterations during colorectal-tumor development.

Vogelstein B, Fearon ER, Hamilton SR, et al.

N Engl J Med. 1988 Sep 1; 319(9):525-32.

Because most colorectal carcinomas appear to arise from adenomas, studies of different stages of colorectal neoplasia may shed light on the genetic alterations involved in tumor progression. We looked for four genetic alterations (ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18) in 172 colorectal-tumor specimens representing various stages of neoplastic development. The specimens consisted of 40 predominantly early-stage adenomas from 7 patients with familial adenomatous polyposis, 40 adenomas (19 without associated foci of carcinoma and 21 with such foci) from 33 patients without familial polyposis, and 92 carcinomas resected from 89 patients. We found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas. However, ras mutations were found in only 9 percent of adenomas under 1 cm in size. Sequences on chromosome 5 that are linked to the gene for familial adenomatous polyposis were not lost in adenomas from the patients with polyposis but were lost in 29 to 35 percent of adenomas and carcinomas, respectively, from other patients. A specific region of chromosome 18 was deleted frequently in carcinomas (73 percent) and in advanced adenomas (47 percent) but only occasionally in earlier-stage adenomas (11 to 13 percent). Chromosome 17p sequences were usually lost only in carcinomas (75 percent). The four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumors. These results are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis

Prediagnostic serum selenium concentration and the risk of recurrent colorectal adenoma: a nested case-control study.

Wallace K, Byers T, Morris JS, et al.

Cancer Epidemiol Biomarkers Prev. 2003 May; 12(5):464-7.

Several studies have suggested that selenium may help to prevent colorectal neoplasia. To investigate the relation between prediagnostic serum selenium concentrations and colorectal adenomas, we conducted a nested case-control study using data from a large, multicenter, adenoma prevention trial. Cases comprised a total of 276 patients who developed a colorectal adenoma between the year 1 and year 4 follow-up exam. Controls were 276 patients who did not develop an adenoma during this time interval, matched to case subjects on age, sex, and clinical center. Total and bound selenium concentrations were measured from baseline or year 1 serum samples using instrumental neutron activation analysis. We estimated the odds ratios of colorectal adenoma in relation to serum selenium concentrations adjusting for age, clinical center, and sex. Compared with the lowest quintile, the odds ratio for the highest quintile was 0.76 (95% confidence interval, 0.44-1.30) for total selenium and 0.60 (95% confidence interval, 0.34-1.05) for bound selenium, and there was no apparent trend in risk (P for trend = 0.50 for total selenium and P for trend = 0.20 for bound selenium). Thus, our findings do not indicate a clear association between serum selenium concentrations and adenoma recurrence

High frequency of activated K-ras codon 15 mutant in colorectal carcinomas from Taiwanese patients.

Wang JY, Hsieh JS, Chen FM, et al.

Int J Cancer. 2003 Nov 10; 107(3):387-93.

Colorectal carcinogenesis is regarded as a multistep process resulting from accumulation of genetic alterations, including activation of protooncogenes and inactivation of tumor suppressor genes via signal transduction trigger the stage-wise progression to malignancy. The reported incidence of K-ras mutation detected in general tissue samples ranges from 21-60% in primary colorectal cancers (CRC). To assess the prevalence and spectrum of K-ras mutations in Taiwanese patients with CRC, we analyzed 65 CRC patients by polymerase chain reaction-single strand conformation polymorphism analysis, followed by direct sequencing. K-ras mutations were detected in 43.1% (28 of 65) of the tumors. The mutational hot spots were located at codons 12, 13, 15 and 20, especially with the highest frequency at codon 15. To understand whether the codon 15 mutations in CRC were associated with activation of K-ras oncogene and the alterations of its biocharacteristics, mutant K-ras genes were cloned from tumor tissues and then inserted into expression vector pBKCMV to construct the prokaryotic expression plasmid pK15MCMV. Mutant K-ras genes were expressed at high levels in E. coli and the mutant K-ras proteins were shown to be functional with respect to their well-known specific, high-affinity, GDP/GTP binding. The purified K-ras protein from E. coli was then measured for its intrinsic GTPase activity and the extrinsic GTPase activity in the presence of GTPase-activating protein for ras. We found that the extrinsic GTPase activity of the codon 15 mutant K-ras proteins (p21(K-ras15M)) in the presence of GAP is much lower than that of the wild-type K-ras protein (p21 BN), whereas the intrinsic GTPase activity is nearly the same as that of the wild-type K-ras protein. The results indicated that mutation at the codon 15 of K-ras gene indeed decreased GTPase activity in CRC, however, its association with tumorigenesis of CRC needs be clarified by further studies

Calcium supplementation decreases rectal epithelial cell proliferation in subjects with sporadic adenoma.

Wargovich MJ, Isbell G, Shabot M, et al.

Gastroenterology. 1992 Jul; 103(1):92-7.

The results of three small clinical trials examining the effect of calcium carbonate supplementation on the proliferation cytokinetics of the rectal epithelium in subjects with a current history of sporadic adenoma are reported. In six subjects, a daily administration of 1500 mg of calcium carbonate for 90 days failed to significantly suppress thymidine labeling in normal-appearing mucosa of the rectum. However, a daily dose of 2000 mg of calcium significantly (P = 0.008) altered mucosal proliferation in a second set of six subjects after a 30-day trial. Finally, a placebo-controlled trial of calcium (2000 mg) was conducted in which 20 subjects were randomized to groups receiving a 4-week intervention with calcium (or placebo), followed by the alternative treatment (placebo or calcium). The results of the study show a marked suppression of rectal proliferation during the calcium phase of the study but not during the placebo phase. This study adds to accumulating evidence showing that calcium supplementation regulates the proliferative behavior of colonic epithelium in the individual at high risk for colon cancer. Longer term trials of calcium supplementation will ascertain whether a continuing benefit from increasing dietary calcium translates into inhibition of adenoma recurrence

Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members.

Watson P, Lin KM, Rodriguez-Bigas MA, et al.

Cancer. 1998 Jul 15; 83(2):259-66.

BACKGROUND: Patients with hereditary nonpolyposis colorectal carcinoma (HNPCC) reportedly have better prognoses than sporadic colorectal carcinoma (CRC) patients, but it has been unclear whether this could be due to differences in stage at diagnosis. The current study compared stage and survival in a retrospective cohort of HNPCC family members who developed CRC with the same factors in an unselected hospital series of patients with sporadic CRC. METHODS: This retrospective cohort study compared HNPCC cases (274 cases from 98 HNPCC families) with an unselected hospital series comprising 820 consecutive CRC cases. All patients were staged according to the TNM system of the American Joint Committee on Cancer and the International Union Against Cancer. Median follow-up among living patients was > 10 years and 8.5 years, respectively, for the two cohorts. Cox regression was used to compare survival in stage-stratified analyses of time from diagnosis to death. RESULTS: Compared with the unselected series, the HNPCC cases had lower stage disease (P < 0.001), and fewer had distant metastases at diagnosis (P < 0.001 in an analysis stratified by T classification). In stage-stratified survival analysis, the HNPCC cases had a significant overall survival advantage regardless of adjustment for their younger age. A conservative estimate of the hazard ratio (of HNPCC cases to the unselected series) was 0.67 (P < 0.0012). CONCLUSIONS: HNPCC patients had lower stage disease at diagnosis than the unselected CRC cases, mainly due to rarer distant metastases at diagnosis. They survived longer than unselected CRC patients with tumors of the same stage. The estimated death rate for the HNPCC cases, adjusted for stage and age differences, was at most two-thirds of the rate for the hospital series

Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) in vivo.

Weber T, Lu M, Andera L, et al.

Clin Cancer Res. 2002 Mar; 8(3):863-9.

Alpha-tocopheryl succinate (alpha-TOS), a redox-inactive analogue of vitamin E, is a strong inducer of apoptosis, whereas alpha-tocopherol (alpha-TOH) lacks apoptogenic activity (J. Neuzil et al., FASEB J., 15: 403-415, 2001). Here we investigated the possible antineoplastic activities of alpha-TOH and alpha-TOS and further explored the potential of alpha-TOS as an antitumor agent. Using nude mice with colon cancer xenografts, we found that alpha-TOH exerted modest antitumor activity and acted by inhibiting tumor cell proliferation. In contrast, alpha-TOS showed a more profound antitumor effect, at both the level of inhibition of proliferation and induction of tumor cell apoptosis. alpha-TOS was nontoxic to normal cells and tissues, triggered apoptosis in p53(-/-) and p21(Waf1/Cip1(-/-)) cancer cells, and exerted a cooperative proapoptotic activity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) due to differences in proapoptotic signaling. Finally, alpha-TOS cooperated with tumor necrosis factor-related apoptosis-inducing ligand in suppression of tumor growth in vivo. Vitamin E succinate is thus a potent and highly specific anticancer agent and/or adjuvant of considerable therapeutic potential

Annual report to the nation on the status of cancer, 1975-2000, featuring the uses of surveillance data for cancer prevention and control 471.

Weir HK, Thun MJ, Hankey BF, et al.

J Natl Cancer Inst. 2003 Sep 3; 95(17):1276-99.

BACKGROUND: The American Cancer Society, the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to update cancer rates and trends in the United States. This report updates statistics on lung, female breast, prostate, and colorectal cancers and highlights the uses of selected surveillance data to assist development of state-based cancer control plans. METHODS: Age-adjusted incidence rates from 1996 through 2000 are from state and metropolitan area cancer registries that met NAACCR criteria for highest quality. Death rates are based on underlying cause-of-death data. Long-term trends and rates for major racial and ethnic populations are based on NCI and CDC data. Incidence trends from 1975 through 2000 were adjusted for reporting delays. State-specific screening and risk factor survey data are from the CDC and other federal and private organizations. RESULTS: Cancer incidence rates for all cancer sites combined increased from the mid-1970s through 1992 and then decreased from 1992 through 1995. Observed incidence rates for all cancers combined were essentially stable from 1995 through 2000, whereas the delay-adjusted trend showed an increase that had borderline statistical significance (P =.05). Increases in the incidence rates of breast cancer in women and prostate cancer in men offset a long-term decrease in lung cancer in men. Death rates for all cancer sites combined decreased beginning in 1994 and stabilized from 1998 through 2000, resulting in part from recent revisions in cause-of-death codes. Death rates among men continued to decline throughout the 1990s, whereas trends in death rates among women were essentially unchanged from 1998 through 2000. Analysis of state data for the leading cancers revealed mixed progress in achieving national objectives for improving cancer screening, risk factor reduction, and decreases in mortality. CONCLUSIONS: Overall cancer incidence and death rates began to stabilize in the mid- to late 1990s. The recent increase in the delay-adjusted trend will require monitoring with additional years of data. Further reduction in the burden of cancer is possible but will require the continuation of strong federal, state, local, and private partnerships to increase dissemination of evidence-based cancer control programs to all segments of the population

Relationship between acetylator status, smoking, and diet and colorectal cancer risk in the north-east of England 474.

Welfare MR, Cooper J, Bassendine MF, et al.

Carcinogenesis. 1997 Jul; 18(7):1351-4.

Some previous studies have suggested that the fast phenotype of the N-acetyltransferase NAT2 may confer susceptibility to colorectal cancer because of greater activation of dietary heterocyclic amines, particularly in individuals who also consume well-done red meat, but other studies have not supported this. We describe a large case-control study examining the interaction between dietary, smoking and drinking habits, and acetylation genotype in relation to susceptibility to colorectal cancer. One-hundred-and-seventy-four incident cases and 174 matched controls were recruited. Genotyping for polymorphisms in NAT2 was performed using a method that detects >95% of slow alleles and data on personal habits were collected using a standardized questionnaire. We found no difference in the frequency of the fast acetylator genotype between cases and controls [odds ratio = 0.95 (95% CI 0.61-1.49)], and analysis by sex, age and site also revealed no difference in acetylator genotype. There was, however, considerable heterogeneity in dietary risk factors between fast and slow acetylators. Analysis by acetylator type shows that recent smoking was more frequent in slow acetylator cases than matched controls [OR = 2.31 (1.16-4.6)] and that heavy alcohol consumption was also more frequent in the slow acetylator cases than controls [OR = 2.5 (1.02-7.29)]. In contrast, frequent fried meat intake was seen more frequently in fast acetylator cases than matched controls [OR = 6.0 (1.34-55)]. The odds ratio for the combination of fast acetylator status and frequent fried meat consumption in cases was 6.04 (1.6-26). Our study suggests that there may be different risk factors for colorectal cancer in slow and fast acetylators, and reveals a new observation that slow acetylators may be at risk of colon cancer from smoking. In our community, the overall effect of acetylator status on colorectal cancer risk is neutral

Vitamin and calcium supplement use is associated with decreased adenoma recurrence in patients with a previous history of neoplasia.

Whelan RL, Horvath KD, Gleason NR, et al.

Dis Colon Rectum. 1999 Feb; 42(2):212-7.

INTRODUCTION: Although some have suggested that certain vitamins or calcium supplements may reduce adenoma recurrence, our own prior retrospective study found no such effects. The purpose of this case-control study was to further investigate whether regular vitamin or calcium supplement intake influenced the incidence of recurrent adenomatous polyps in patients with previous neoplasia who were undergoing follow-up colonoscopy. METHODS: This study enrolled 1,162 patients who underwent colonoscopy by one of three surgeons at Columbia-Presbyterian Medical Center in New York City between March 1993 and February 1997. Of these patients 448 (250 males) had a previous diagnosis of colorectal neoplasia (cancer, adenomas, or dysplasia). Of these, 183 (40.8 percent) had an adenoma at the index colonoscopy. Information was collected on personal and family history of colonic diseases, cigarette smoking, medication, and vitamin and micronutrient supplement usage on a questionnaire that was completed by the patients before the colonoscopy. Odds ratios were obtained by unconditional logistic regression analysis, adjusting for age and gender, and used adenoma recurrence at index colonoscopy as the outcome. RESULTS: The mean interval between colonoscopic examinations was 37 months for the recurrent adenoma group and 38 months for the nonrecurrent group of patients (P = not significant). In this case-control study we found a protective effect for the use of vitamin supplements in general (any vitamin) on the recurrence of adenomas (odds ratio, 0.41; 95 percent confidence interval, 0.27-0.61). Specifically, this protective effect was observed for the use of multivitamins (odds ratio, 0.47; 95 percent confidence interval, 0.31-0.72), vitamin E (odds ratio, 0.62; 95 percent confidence interval, 0.39-0.98), and for calcium supplementation (odds ratio, 0.51; 95 percent confidence interval, 0.27-0.96). Nonsignificant protective effects were noted for carotene/vitamin A, vitamin D, and vitamin C. CONCLUSIONS: The use of multivitamins, vitamin E, and calcium supplements were found to be associated with a lower incidence of recurrent adenomas in a population of patients with history of previous colonic neoplasia. Prospective, randomized trials are needed to better assess the impact of these agents and to determine whether the use of these supplements is associated with a protective effect against recurrent adenomas

A comparison of the 25-cm rigid proctosigmoidoscope with the 65-cm flexible endoscope in the screening of patients for colorectal carcinoma.

Wilking N, Petrelli NJ, Herrera-Ornelas L, et al.

Cancer. 1986 Feb 1; 57(3):669-71.

A comparison of the rigid with the flexible sigmoidoscope was evaluated in 293 patients as part of a screening project for colorectal cancer at Roswell Park Memorial Institute. Patients with either a positive family history for colorectal cancer, a positive stool guaiac test result, a history of hematochezia, or a change in bowel habits were randomly assigned to either rigid or flexible sigmoidoscopy. The median distance of colon examined with the flexible instrument was significantly greater than with the rigid scope (55 versus 17 cm, respectively). A significantly greater number of malignant and premalignant lesions were found with the flexible instrument than with the rigid scope. It was concluded that the flexible sigmoidoscope is superior to the rigid scope in the process of screening for colorectal lesions

Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) is induced by genistein through the expression of p53 in colorectal cancer cells.

Wilson LC, Baek SJ, Call A, et al.

Int J Cancer. 2003 Jul 20; 105(6):747-53.

Genistein is an isoflavenoid found in soy that has anti-tumorigenic activities. Treatment of colorectal carcinoma HCT-116 cells with 50 microM genistein results in a 50% reduction in cell proliferation and a 6-fold increase in apoptosis. Genistein induces nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1), a protein with antitumorigenic activities, in a time- and concentration-dependent manner in HCT-116 cells. In addition, p53 and p21 are induced in HCT-116 cells. The induction of p53 (3 hr) precedes the induction of NAG-1 (12 hr), suggesting that genistein-induced NAG-1 expression is mediated by p53. In contrast, NAG-1 is not induced by genistein in the p53-negative colorectal carcinoma cell line HCT-15. Luciferase reporter constructs of the NAG-1 promoter containing 2 p53 sites showed that the p53 sites within the NAG-1 promoter are critical to genistein-induced NAG-1 expression in p53-positive U2OS cells. The expression of p53 was critical for NAG-1 promoter activity since no promoter activity was observed with genistein treatment in HCT-15 cells. However, genistein-induced promoter activity was restored in HCT-15 cells by transfection with wild-type p53. Together our data suggest a relationship between genistein, p53 and NAG-1 forming a novel pathway responsible for the antitumorigenic activity of genistein

A pioneer in flexible sigmoidoscopy.

Winawer SJ.

Gastroenterology. 1977 Nov; 73(5):1190-1.

Screening of average-risk individuals for colorectal cancer. WHO Collaborating Centre for the Prevention of Colorectal Cancer.

Winawer SJ, St John J, Bond J, et al.

Bull World Health Organ. 1990; 68(4):505-13.

Recent developments in screening, diagnosis and treatment of colon cancer could lead to a reduction in mortality from this disease. Removal of adenomas, identification of risk factors, appropriate application of accurate diagnostic tests, and aggressive anatomic-surgical resection of colon cancers may already be having a favourable impact. Screening of average-risk populations over the age of 50 also offers promise in the control of this important cancer. The disease is of sufficient magnitude to deserve detection at an early stage with better prospects of patient survival, since screening tests with moderate sensitivity and high specificity are available. Flexible sigmoidoscopy and faecal occult blood tests are sufficiently acceptable to be included in case-finding among patients who are in the health care system. The results of current controlled trials involving more than 300,000 individuals for evaluating the impact of screening on mortality from colon cancer are needed before this approach can be recommended for general public health screening of the population. Further research is required to develop better screening tests, improve patient and physician compliance, and answer more definitively critical questions on cost-effectiveness. Mathematical modelling using current and new data can be used to determine the effectiveness of screening in conjunction with recommendations for primary prevention

Colorectal cancer screening.

Winawer SJ, Schottenfeld D, Flehinger BJ.

J Natl Cancer Inst. 1991 Feb 20; 83(4):243-53.

Dietary factors in colorectal cancer and their possible effects on earlier stages of hyperproliferation and adenoma formation 473.

Winawer SJ, Shike M.

J Natl Cancer Inst. 1992 Jan 15; 84(2):74-5.

Prevention of Colorectal Cancer by Colonoscopic Polypectomy.

Winawer SJ, Zauber AG, Ho MN, et al.

N Engl J Med. 1993 Dec 30; 329(27):1977-81.

Background The current practice of removing adenomatous polyps of the colon and rectum is based on the belief that this will prevent colorectal cancer. To address the hypothesis that colonoscopic polypectomy reduces the incidence of colorectal cancer, we analyzed the results of the National Polyp Study with reference to other published results. Methods The study cohort consisted of 1418 patients who had a complete colonoscopy during which one or more adenomas of the colon or rectum were removed. The patients subsequently underwent periodic colonoscopy during an average follow-up of 5.9 years, and the incidence of colorectal cancer was ascertained. The incidence rate of colorectal cancer was compared with that in three reference groups, including two cohorts in which colonic polyps were not removed and one general-population registry, after adjustment for sex, age, and polyp size. Results Ninety-seven percent of the patients were followed clinically for a total of 8401 person-years, and 80 percent returned for one or more of their scheduled colonoscopies. Five asymptomatic early-stage colorectal cancers (malignant polyps) were detected by colonoscopy (three at three years, one at six years, and one at seven years). No symptomatic cancers were detected. The numbers of colorectal cancers expected on the basis of the rates in the three reference groups were 48.3, 43.4, and 20.7, for reductions in the incidence of colorectal cancer of 90, 88, and 76 percent, respectively (P<0.001). Conclusions Colonoscopic polypectomy resulted in a lower-than-expected incidence of colorectal cancer. These results support the view that colorectal adenomas progress to adenocarcinomas, as well as the current practice of searching for and removing adenomatous polyps to prevent colorectal cancer

Alpha-fetoprotein-producing carcinoma of the colon: report of a case and review of the literature.

Yachida S, Fukushima N, Nakanishi Y, et al.

Dis Colon Rectum. 2003 Jun; 46(6):826-31.

PURPOSE: We describe a rare case of an alpha-fetoprotein-producing carcinoma originating in the transverse colon of a 59-year-old Japanese male. METHODS: The patient reported an abdominal mass and weight loss. On examination, a tumor of the transverse colon and multiple masses in the liver were found. The serum alpha-fetoprotein level was extremely high (12,873 ng/ml). The patient underwent right hemicolectomy and intraoperative biopsy of a liver mass. RESULTS: Histologically, the colon cancer was composed of three different components: a well-differentiated tubular adenocarcinoma, a tubulopapillary carcinoma consisting of cells with clear cytoplasms, and a "hepatoid carcinoma." The hepatoid carcinoma was composed of large polygonal cells with abundant eosinophilic or clear cytoplasms, arranged in a trabecular or solid pattern, and showing marked vascular invasion. Immunohistochemically, alpha-fetoprotein was strongly expressed, largely in the hepatoid carcinoma and partially in the tubulopapillary carcinoma. The liver biopsy specimen showed morphologic and immunohistochemical features similar to those of the hepatoid carcinoma of the colon and was therefore diagnosed as a metastasis. The patient died of the cancer two months after surgery. CONCLUSION: Based on our experience of this patient and a review of the literature, alpha-fetoprotein-producing colorectal carcinomas are generally associated with a poor prognosis because of the frequent occurrence of blood-borne metastases

[The effect of omega-3 fatty acids on risk factors for cardiovascular diseases].

Yam D, Bott-Kanner G, Genin I, et al.

Harefuah. 2001 Dec; 140(12):1156-8, 1230.

Cardiovascular disease (CVD) is associated with dyslipidemia and frequently with insulin resistance, both of which are in general no alleviated by antilipidemic drugs. Our objective was to examine whether a dietary supplement containing omega-3 fatty acids (n-3 FA) can reduce the levels of serum lipids, fasting insulin and glucose in documented CVD patients treated by statins or bezafibrates. In a double-blind placebo-controlled trial of parallel design, 52 patients, age 69.2 years +/- 3.6 treated by antilipidemic drugs, were randomly assigned to receive daily 7 gr of a dietary concentrated supplement containing 67% n-3 FA (185 mg EPA and 465 mg/g DHA) in a form of spread (Yamega Ltd, Israel) or olive oil spread (placebo) and recommended to reduce the consumption of omega-6 fatty acids for 12 weeks. The average values +/- SD before and after dietary supplementations were compared. RESULTS: 44 patients (23 in the n-3 FA group) completed the study. In the n-3FA group we observed a significant decrease (p < 0.05) of total cholesterol (12.2%). LDL-cholesterol (16.8%), triglycerides (36.1%), insulin in hyperinsulinemic subjects (> 20 microunits/ml) (34.9%), and no significant changes in HDL-cholesterol and glucose. No hyperglycemia was detected. In the olive oil group we observed a significant decrease (p < 0.05) in the LDL-cholesterol values of 15.5% and no significant changes in the other parameters. No side effects were reported during the study in any of the participants. Our findings demonstrate that the incorporation of the dietary supplement containing EPA and DHA omega-3 fatty acids reduces significantly the above risk factors for CVD

Blood and urine levels of tea catechins after ingestion of different amounts of green tea by human volunteers.

Yang CS, Chen L, Lee MJ, et al.

Cancer Epidemiol Biomarkers Prev. 1998 Apr; 7(4):351-4.

The inhibitory activity of tea against tumorigenesis has been demonstrated in many animal models and has been suggested by some epidemiological studies. Such activity has generally been attributed to tea catechins. To understand the bioavailability of tea catechins in humans, we gave 18 individuals different amounts of green tea and measured the time-dependent plasma concentrations and urinary excretion of tea catechins. After taking 1.5, 3.0, and 4.5 g of decaffeinated green tea solids (dissolved in 500 ml of water), the maximum plasma concentration (Cmax) of (-)-epigallocatechin-3-gallate (EGCG) was 326 ng/ml, the Cmax of (-)-epigallocatechin (EGC) was 550 ng/ml, and the Cmax of (-)-epicatechin (EC) was 190 ng/ml. These Cmax values were observed at 1.4-2.4 h after ingestion of the tea preparation. When the dosage was increased from 1.5 to 3.0 g, the Cmax values increased 2.7-3.4-fold, but increasing the dose to 4.5 g did not increase the Cmax values significantly, which suggested a saturation phenomenon. The half-life of EGCG (5.0-5.5 h) seemed to be higher than the half-life of EGC or EC (2.5-3.4 h). EGC and EC, but not EGCG, were excreted in the urine. Over 90% of the total urinary EGC and EC was excreted within 8 h. When the tea dosage was increased, the amount of EGC and EC excretion seemed to increase, but a clear dose-response relationship was not observed. The present study provides basic pharmacokinetic parameters of green tea catechins in humans; these parameters may be used to estimate the levels of these compounds after drinking tea

American Joint Committee on Cancer prognostic factors consensus conference.

Yarbro JW, Page DL, Fielding LP, et al.

Cancer. 1999 Dec 1; 86(11):2436-46.

BACKGROUND: The American Joint Committee on Cancer (AJCC) published the 1st edition of the Cancer Staging Manual in 1977 and began using T (tumor extent), N (regional lymph node status), and M (the presence or absence of distant metastasis) in an organized staging scheme to express the extent of disease in a number of cancer sites. The goal of this program has been to provide physicians and others with a useful methodology to plan treatment, project prognosis, and measure outcome end results. Until recent years, this system has incorporated only elements of anatomic extent of the tumors determined by clinical and pathologic methods. At the present time an increasing number of nonanatomic cancer prognostic factors are being identified and studied. Some of these factors currently are being used for outcome predictions and treatment decisions. METHODS: To begin the process of identifying and validating these prognostic factors to refine the present TNM system, the AJCC convened a Prognostic Factors Consensus Conference to evaluate the roles of biologic, genetic, molecular, and other nonanatomic factors in staging cancer. Working groups were appointed for carcinomas of the breast, colorectum, prostate, and ovary and experts in each of these areas were invited to participate. Emphasis was placed on evaluating existing data and the correlation of these data with survival. RESULTS: None of the groups believed that there were sufficient data at the present time to merit incorporation of serum markers into the TNM system for the four tumors under consideration, although this soon might become possible in prostate carcinoma after the evaluation of survival data from multiple institutions. Recommendations were made regarding the emerging sentinel lymph node technique, the need for an increased use of histopathology in the staging of breast and ovarian carcinomas, and the use of additional histologic staining techniques for the detection of "micrometastases" in lymph nodes. A number of additional recommendations were made for changes to the TNM system that did not involve serum markers and other nonanatomic cancer prognostic factors. CONCLUSIONS: These recommendations are presented for the purpose of discussion and evaluation and do not yet represent formal proposals for a change in the AJCC TNM system of staging

[Effect of cimetidine with chemotherapy on stage IV colorectal cancer].

Yoshimatsu K, Ishibashi K, Hashimoto M, et al.

Gan To Kagaku Ryoho. 2003 Oct; 30(11):1794-7.

We herein report the result of a prospective study to investigate the efficacy of cimetidine administration in conjunction with chemotherapy for stage IV colorectal cancer. Sixty-two patients treated with Leucovorin/5-fluorouracil therapy were enrolled from 1996 to 2000. Both groups were well matched for pre-treatment characteristics. There was no difference in survival in cur B patients. However, the cimetidine group had significantly prolonged survival in the patients with cur C or non-resectable carcinoma. This study suggests that cimetidine treatment may improve the survival of patients with non-curative surgery for stage IV colorectal cancer

Induction of apoptosis in human breast cancer cells by tocopherols and tocotrienols.

Yu W, Simmons-Menchaca M, Gapor A, et al.

Nutr Cancer. 1999; 33(1):26-32.

The apoptosis-inducing properties of RRR-alpha-, beta-, gamma-, and delta-tocopherols, alpha-, gamma-, and delta-tocotrienols, RRR-alpha-tocopheryl acetate (vitamin E acetate), and RRR-alpha-tocopheryl succinate (vitamin E succinate) were investigated in estrogen-responsive MCF7 and estrogen-nonresponsive MDA-MB-435 human breast cancer cell lines in culture. Apoptosis was characterized by two criteria: 1) morphology of 4,6-diamidino-2-phenylindole-stained cells and oligonucleosomal DNA laddering. Vitamin E succinate, a known inducer of apoptosis in several cell lines, including human breast cancer cells, served as a positive control. The estrogen-responsive MCF7 cells were more susceptible than the estrogen-nonresponsive MDA-MB-435 cells, with concentrations for half-maximal response for tocotrienols (alpha, gamma, and delta) and RRR-delta-tocopherol of 14, 15, 7, and 97 micrograms/ml, respectively. The tocotrienols (alpha, gamma, and delta) and RRR-delta-tocopherol induced MDA-MB-435 cells to undergo apoptosis, with concentrations for half-maximal response of 176, 28, 13, and 145 micrograms/ml, respectively. With the exception of RRR-delta-tocopherol, the tocopherols (alpha, beta, and gamma) and the acetate derivative of RRR-alpha-tocopherol (RRR-alpha-tocopheryl acetate) were ineffective in induction of apoptosis in both cell lines when tested within the range of their solubility, i.e., 10-200 micrograms/ml. In summary, these studies demonstrate that naturally occurring tocotrienols and RRR-delta-tocopherol are effective apoptotic inducers for human breast cancer cells

Serosal cytologic study to determine free mesothelial penetration of intraperitoneal colon cancer.

Zeng Z, Cohen AM, Hajdu S, et al.

Cancer. 1992 Aug 15; 70(4):737-40.

BACKGROUND. The presence of complete transmural penetration with tumor cells at the free mesothelial surface in patients with intraperitoneal colon cancer is an important prognostic feature and may alter the decision regarding adjuvant chemotherapy. METHODS. In this prospective study of 65 patients, specimens obtained by scraping the serosa overlying the primary tumor mass were analyzed by routine Papanicolaou cytologic study. RESULTS. Malignant cells were present in 23.1% of patients. In 46 patients with histologic pT3 tumors (through the muscularis propria but not through serosa), serosal cytologic study results were positive in 26.1% of patients. Serosal cytologic results were positive from an area of normal colon at least 10 cm proximal or distal to the primary tumor in one patient. CONCLUSIONS. Serosal cytologic study appeared to be a simple and reliable method to detect serosal penetration and the presence of tumor cells at the mesothelial surface

[Study of angiogenesis in human colorectal carcinoma and its modulation by p53 and K-ras gene].

Zhong SS, Zhang ZS, Li SM, et al.

Zhonghua Nei Ke Za Zhi. 2003 Feb; 42(2):77-80.

OBJECTIVE: To investigate the angiogenesis in human colorectal carcinoma and its modulation by p53 and K-ras gene. METHODS: The positive rate of p53 and K-ras gene mutation, the expression of vascular endothelial growth factor (VEGF) and microvessel density in 68 cancer tissue, peritumoral tissue samples and 20 normal controls were studied by PCR-SSCP and immunohistochemical methods. RESULTS: The positive rate of p53 and K-ras gene mutation and the expression of VEGF in cancer tissue (47.1%, 32/68; 44.1%, 30/68; 55.9%, 38/68) were significantly higher than in peritumoral tissue (13.2%, 9/68; 7.4%, 5/68; 11.8%, 8/68). p53, K-ras gene mutation and the expression of VEGF were not detected in 20 normal tissue. The expression of VEGF was closely related with the angiogenesis and metastasis of colorectal carcinoma (r = 0.820, P < 0.01). VEGF expression correlated with both p53 and K-ras gene mutation (P < 0.01). CONCLUSIONS: p53 and K-ras gene upregulated the expression of VEGF. p53 and K-ras gene might play an important role in modulating tumor angiogenesis