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PROSTATE CANCER
EARLY STAGE
(Page 3)


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book The potential role of lycopene for human health
book Lycopene: A biologically important carotenoid for humans?
book cis-trans lycopene isomers, carotenoids, and retinol in the human prostate
book How is individual risk for prostate cancer assessed?
book A tomato a day for preventing prostate cancer? Diet may be key
book Intake of carotenoids and retinol in relation to risk of prostate cancer
book Whatever happened to beta carotene?
book Vegetable and fruit consumption in relation to prostate cancer risk in Hawaii: A reevaluation of the effect of dietary beta-carotene
book Serologic precursors of cancer. Retinol, carotenoids, and tocopherol and risk of prostate cancer
book Carcinogenicity of oral cadmium in the male Wistar (WF/NCr) rat: Effect of chronic dietary zinc deficiency
book Nutrition and prostate cancer: A case-control study
book Zinc, vitamin A and prostatic cancer
book Influence of isoflavones in soy protein isolates on development of induced prostate-related cancers in L-W rats
book Peptide growth factors: Clinical and therapeutic strategies
book Cancer risk factors for selecting cohorts for large-scale chemoprevention trials
book Inhibition of liposomal lipid peroxidation by isoflavonoid type phyto-oestrogens from soybeans of different countries of origin
book Phytoestrogens: Epidemiology and a possible role in cancer protection
book Differential sensitivity of human prostatic cancer cell lines to the effects of protein kinase and phosphatase inhibitors
book Genetic damage and the inhibition of 7,12-dimethylbenz(a)anthracene-induc ed genetic damage by the phytoestrogens, genistein and daidzein, in female ICR mice
book Rationale for the use of genistein-containing soy matrices in chemoprevention trials for breast and prostate cancer
book A simplified method to quantify isoflavones in commercial soybean diets and human urine after legume consumption
book Rapid HPLC analysis of dietary phytoestrogens from legumes and from human urine
book Soy intake and cancer risk: A review of the in vitro and in vivo data
book Plasma concentrations of phyto-oestrogens in Japanese men
book Genistein is an effective stimulator of sex hormone-binding globulin production in hepatocarcinoma human liver cancer cells and suppresses proliferation of these cells in culture
book Genistein and biochanin A inhibit the growth of human prostate cancer cells but not epidermal growth factor receptor tyrosine autophosphorylation
book Surrogate endpoint biomarkers for phase II cancer chemoprevention trials
book The 16-ene vitamin D analogs
book Signal transduction inhibitors as modifiers of radiation therapy in human prostate carcinoma xenografts
book Calcium regulation of androgen receptor expression in the human prostate cancer cell line LNCaP
book The role of calcium, pH, and cell proliferation in the programmed (apoptotic) death of androgen-independent prostatic cancer cells induced by thapsigarin
book Programmed cell death as a new target for prostatic cancer therapy
book Hyperparathyroidism in metastases of prostatic carcinoma: A biochemical, hormonal and histomorphometric study
book In vitro studies of human prostatic epithelial cells: Attempts to identify distinguishing features of malignant cells
book Hypocalcemia associated with estrogen therapy for metastatic adenocarcinoma of the prostate
book Hypercalcemia in carcinoma of the prostate: Case report and review of the literature
book Calcium excretion in metastatic prostatic carcinoma
book Osteomalacia associated with prostatic cancer and osteoblastic metastases
book Carcinoma of the prostate: The treatment of bone metastases by radiophosphorus
book Management of cancer of the prostate
book Intracavitary irradiation of prostate carcinomas
book Epidemiology of prostatic cancer: A case-control study
book Demonstration of specifically sensitized lymphocytes in patients treated with an aqueous mistletoe extract (Viscum album L.)
book An urodynamic study of patients with benign prostatic hypertrophy treated conservatively with phytotherapy or testosterone


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The potential role of lycopene for human health

Gerster H.
H. Gerster, Vitamin Research Department, F. Hoffmann-LaRoche Ltd, Bldg 73/30A, CH-4070 Basel Switzerland
Journal of the American College of Nutrition (USA), 1997, 16/2 (109-126)

Lycopene is one of the major carotenoids in Western diets and is found almost exclusively in tomatoes and tomato products. It accounts for about 50% of carotenoids in human serum. Among the common dietary carotenoids lycopene has the highest singlet oxygen quenching capacity in vitro. Other outstanding features are its high concentration in testes, adrenal gland and prostate. In contrast to other carotenoids its serum values are not regularly reduced by smoking or alcohol consumption but by increasing age. Remarkable inverse relation ships between lycopene intake or serum values and risk have been observed in particular for cancers of the prostate, pancreas and to a certain extent of the stomach. In some of the studies lycopene was the only carotenoid associated with risk reduction. Its role in cancer risk reduction still needs to be clarified. Patients with HIV infection, inflammatory diseases and hyperlipidemia with and without lipid lowering treatment may have depleted lycopene serum concentrations. Before embarking on large-scale human trials the distribution of lycopene and its biological functions need to be further evaluated.



Lycopene: A biologically important carotenoid for humans?

Stahl W.; Sies H.
Germany
Archives of Biochemistry and Biophysics (USA), 1996, 336/1 (1-9)

Lycopene is a carotenoid present in human blood (similar0.5 micromol/liter plasma), and the tissue levels vary from 1 nmol/g wet wt in adipose tissue to up to 20 nmol/g wet wt in adrenals and testes. Its biological activities include antioxidant activity (singlet oxygen quenching and peroxyl radical scavenging), induction of cell-cell communication, and growth control, but no provitamin A activity. Epidemiological studies suggest protective effects of lycopene on some types of cancer, e.g., prostate cancer. In vitro and in vivo studies on growth of tumor cells support this conclusion. The major sources of lycopene for the human are tomatoes and tomato products, and bioavailability from different food items varies considerably. Lycopene oxidation products have recently been identified in human serum. Suggested health effects of lycopene require further investigation.



cis-trans lycopene isomers, carotenoids, and retinol in the human prostate

Clinton S.K.; Emenhiser C.; Schwartz S.J.; Bostwick D.G.; Williams A.W.; Moore B.J.; Erdman J.W. Jr.
Dana-Farber Cancer Institute, Dana Building, 44 Binney Street, Boston, MA 02115-6084 USA
Cancer Epidemiology Biomarkers and Prevention (USA), 1996, 5/10 (823-833)

An evaluation of the Health Professionals Follow-Up Study has detected a lower prostate cancer risk associated with the greater consumption of tomatoes and related food products. Tomatoes are the primary dietary source of lycopene, a non-provitamin A carotenoid with potent antioxidant activity. Our goal was to define the concentrations of lycopene, other carotenoids, and retinol in paired benign and malignant prostate tissue from 25 men, ages 53 to 74, undergoing prostatectomy for localized prostate cancer. The concentrations of specific carotenoids in the benign and malignant prostate tissue from the same subject are highly correlated. Lycopene and all-trans beta-carotene are the predominant carotenoids observed, with means plus or minus SE of 0.80 plus or minus 0.08 nmol/g and 0.54 plus or minus 0.09, respectively. Lycopene concentrations range from 0 to 2.58 nmol/g, and all-trans beta-carotene concentrations range from 0.09 to 1.70 nmol/g. The 9-cis beta-carotene isomer, alpha-carotene, lutein, alpha-cryptoxanthin, zeaxanthin, and beta-cryptoxanthin are consistently detectable in prostate tissue. No significant correlations between the concentration of lycopene and the concentrations of any other carotenoid are observed. In contrast, strong correlations between prostate beta-carotene and alpha-carotene are noted (correlation coefficient, 0.88; P < 0.0001), as are correlations between several other carotenoid pairs, which reflects their similar dietary origins. Mean vitamin A concentration in the prostate is 1.52 nmol/g, with a range of 0.71 to 3.30 nmol/g. We further evaluated tomato- based food products, serum, and prostate tissue for the presence of geometric lycopene isomers using high-performance liquid chromatography with a polymeric C30 reversed phase column. All-trans lycopene accounts for 79 to 91% and cis lycopene isomers for 9 to 21% of total lycopene in tomatoes, tomato paste, and tomato soup. Lycopene concentrations in the serum of men range between 0.60 and 1.9 nmol/ml, with 27 to 42% all-trans lycopene and 58 to 73% cis-isomers distributed among 12 to 13 peaks, depending upon their chromatographic resolution. In striking contrast with foods, all-trans lycopene accounts for only 12 to 21% and cis isomers for 79 to 88% of total lycopene in benign or malignant prostate tissues. cis Isomers of lycopene within the prostate are distributed among 14 to 18 peaks. We conclude that a diverse array of carotenoids are found in the human prostate with significant intra-individual variation. The presence of lycopene in the prostate at concentrations that are biologically active in laboratory studies supports the hypothesis that lycopene may have direct effects within the prostate and contribute to the reduced prostate cancer risk associated with the consumption of tomato-based foods. The future identification and characterization of geometric lycopene isomers may lead to the development of novel agents for chemoprevention studies.



How is individual risk for prostate cancer assessed?

Giovannucci E.
Channing Laboratory, 180 Longwood Avenue, Boston, MA 02115 USA
Hematology/Oncology Clinics of North America (USA), 1996, 10/3 (537-548)

A man's risk of developing prostate cancer is influenced by both genetic and nongenetic factors. Genetic factors are particularly important at younger ages, and the attributable risk of strong genetic factors could be as high as 43% among men less than 55 years of age; however, only about 9%, of all cases may be directly attributable to a family history of prostate cancer. Race appears to be an important determinant of risk; African-American men are at high risk, whereas men of oriental ancestry are at lower risk. The bases of these racial differences remain obscure but may be related to hormonal differences. Modifiable risk factors are most important from a public health perspective. Diet or closely related factors appear to hold the most promise for prevention, although the precise factors are unknown. The strongest evidence indicates that some component of animal fat intake appears to act as a promoter of prostate cancer. Other dietary factors, including vitamin D, vitamin E, and beta-carotene and lycopene, may confer protection, but these require more study. Many but not all studies that have examined long-term effects of vasectomy suggest that this procedure may increase risk of prostate cancer, but whether this association is causal is not established. Occupational factors, smoking, and physical activity level do not appear to be major determinants of prostate cancer risk.



A tomato a day for preventing prostate cancer? Diet may be key

No author listed.
Geriatrics (USA), 1996, 51/2 (21)

No abstract.



Intake of carotenoids and retinol in relation to risk of prostate cancer

Giovannucci E.; Ascherio A.; Rimm E.B.; Stampfer M.J.; Colditz G.A.; Willett W.C.
Channing Laboratory, 180 Longwood Ave., Boston, MA 02115 USA
Journal of the National Cancer Institute (USA), 1995, 87/23 (1767-1776)

Background: Several human studies have observed a direct association between retinol (vitamin A) intake and risk of prostate cancer; other studies have found either an inverse association or no association of intake of beta- carotene (the major provitamin A) with risk of prostate cancer. Data regarding carotenoids other than beta-carotene in relation to prostate cancer risk are sparse.

Purpose: We conducted a prospective cohort study to examine the relationship between the intake of various carotenoids, retinol, fruits, and vegetables and the risk of prostate cancer.

Methods: Using responses to a validated, semiquantitative food-frequency questionnaire mailed to participants in the Health Professionals Follow-up Study in 1986, we assessed dietary intake for a 1-year period for a cohort of 47 894 eligible subjects initially free of diagnosed cancer. Follow-up questionnaires were sent to the entire cohort in 1988, 1990, and 1992. We calculated the relative risk (RR) for each of the upper categories of intake of a specific food or nutrient by dividing the incidence rate of prostate cancer among men in each of these categories by the rate among men in the lowest intake level. All P values resulted from two-sided tests.

Results: Between 1986 and 1992, 812 new cases of prostate cancer, including 773 non-stage A1 cases, were documented. Intakes of the carotenoids beta-carotene, alpha-carotene, lutein, and beta- cryptoxanthin were not associated with risk of non-stage A1 prostate cancer; only lycopene intake was related to lower risk (age- and energy-adjusted RR = 0.79; 95% confidence interval (CI) = 0.64-0.99 for high versus low quintile of intake; P for trend = .04). Of 46 vegetables and fruits or related products, four were significantly associated with lower prostate cancer risk; of the four-tomato sauce (P for trend = .001), tomatoes (P for trend = .03), and pizza (P for trend = .05), but not strawberries-were primary sources of lycopene. Combined intake of tomatoes, tomato sauce, tomato juice, and pizza (which accounted for 82% of lycopene intake) was inversely associated with risk of prostate cancer (multivariate RR = 0.65; 95% CI = 0.44-0.95, for consumption frequency greater than 10 versus less than 1.5 servings per week; P for trend = .01) and advanced (stages C and D) prostate cancers (multivariate RR = 0.47; 95% CI = 0.22-1.00; P for trend = .03). No consistent association was observed for dietary retinol and risk of prostate cancer.

Conclusions: These findings suggest that intake of lycopene or other compounds in tomatoes may reduce prostate cancer risk, but other measured carotenoids are unrelated to risk. Implications: Our findings support recommendations to increase vegetable and fruit consumption to reduce cancer incidence but suggest that tomato-based foods may be especially beneficial regarding prostate cancer risk.



Whatever happened to beta carotene?

Holzman D.
Journal of the National Cancer Institute (USA), 1995, 87/23 (1739-1741)

No abstract.



Vegetable and fruit consumption in relation to prostate cancer risk in Hawaii: A reevaluation of the effect of dietary beta-carotene

Le Marchand L.; Hankin J.H.; Kolonel L.N.; Wilkens L.R.
Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, 1236 Lauhala Street, Honolulu, HI 96813 USA
Am. J. Epidemiol. (USA), 1991, 133/3 (215-219)

This is a further analysis of a case-control study of 452 prostate cancer cases and 899 population controls that was conducted in 1970-1983 among the multiethnic population of Hawaii. Because a previous analysis had shown a positive association with intake of beta-carotene, a nutrient presently being tested for chemoprevention, the authors reexamined the data for consistency among the main food sources of beta-carotene. Vegetables and fruits containing other phytochemicals suspected to be cancer inhibitors were also examined. With the exception of papaya, which was positively associated with risk among men aged 70 years and older, consumption of other yellow-orange fruits and vegetables, tomatoes, dark green vegetables, and cruciferous vegetables was not associated with prostate cancer risk. These results suggest that: 1) the positive association with beta-carotene intake among older men that the authors previously reported was essentially due to the greater papaya consumption of cases compared with controls; and 2) intake of beta-carotene, lycopene, lutein, indoles, phenols, or other phytochemicals is not associated with prostate cancer risk.



Serologic precursors of cancer. Retinol, carotenoids, and tocopherol and risk of prostate cancer

Hsing A.W.; Comstock G.W.; Abbey H.; Polk B.F.
Training Center for Public Health Research, Box 2067, Hagerstown, MD 21742-2067 USA
J. Natl. Cancer Inst. (USA), 1990, 82/11 (941-946)

We investigated the associations of serum retinol, the carotenoids beta-carotene and lycopene, and tocopherol (vitamin E) with the risk of prostate cancer in a nested case-control study. For the study, serum obtained in 1974 from 25,802 persons in Washington County, MD, was used. Serum levels of the nutrients in 103 men who developed prostate cancer during the subsequent 13 years were compared with levels in 103 control subjects matched for age and race. Although no significant associations were observed with beta-carotene, lycopene, or tocopherol, the data suggested an inverse relationship between serum retinol and risk of prostate cancer. We analyzed data on the distribution of serum retinol by quartiles, using the lowest quartile as the reference value. Odds ratios were 0.67, 0.39, and 0.40 for the second, third, and highest quartiles, respectively.



Carcinogenicity of oral cadmium in the male Wistar (WF/NCr) rat: Effect of chronic dietary zinc deficiency

Waalkes M.P.; Rehm S.
Lab. of Comparative Carcinogenesis, NCI-FCRDC, Frederick, MD 21702-1201 USA
Fundam. Aappl Toxicol. (USA), 1992, 19/4 (512-520)

The effect of chronic dietary zinc deficiency on the carcinogenic potential of dietary cadmium was assessed in male Wistar (WF/NCr) rats. Groups (n = 28) of rats were fed diets adequate (60 ppm) or marginally deficient (7 ppm) in zinc and containing cadmium at various levels (0, 25, 50, 100, or 200 ppm). Lesions were assessed over the following 77 weeks. Zinc deficiency alone had no effect on survival, growth, or food consumption. Cadmium treatment did not reduce survival or food consumption and only at the highest doses of cadmium (100 and 200 ppm) was body weight reduced (maximum 17%). The incidence of prostatic proliferative lesions, both hyperplasias and adenomas, was increased over that seen in controls (1.8%) in both zinc-adequate (20%) and zinc-deficient rats (14%) fed 50 ppm cadmium. The overall incidence for prostatic lesions for all cadmium treatment groups was, however, much lower in zinc-deficient rats, possibly because of a marked increase in prostatic atrophy that was associated with reduced zinc intake. Cadmium treatment resulted in an elevated leukemia incidence (maximum 4.8-fold over control) in both zinc-adequate and zinc-deficient groups, although zinc deficiency reduced the potency of cadmium in this respect. Testicular tumors were significantly elevated only in rats receiving 200 ppm cadmium and diets adequate in zinc. Both zinc-deficient and zinc-adequate groups showed significant positive trends for development of testicular neoplasia with increasing cadmium dosage. Thus, oral cadmium exposure is clearly associated with tumors of the prostate, testes, and hematopoietic system in rats, while dietary zinc deficiency has complex, apparently inhibitory, effects on cadmium carcinogenesis by this route.



Nutrition and prostate cancer: A case-control study

Heshmat M.Y.; Kaul L.; Kovi J.; et al.
Department of Community Health and Family Practice, Howard University College of Medicine, Washington, DC 20059 USA
Prostate (USA), 1985, 6/1 (7-17)

No abstract.



Zinc, vitamin A and prostatic cancer

Whelan P.; Walker B.E.; Kelleher J.
Dep. Urol., St. James's Univ. Hosp., Leeds LS9 7TF United Kingdom
Br. J. Urol. (England), 1983, 55/5 (525-528)

The serum zinc, vitamin A, albumin, copper and retinoid-binding protein content was measured in 27 patients with benign prostatic hyperplasia and 19 patients with carcinoma of the prostate. A significantly lower (P = < 0.05) level of serum zinc was found in the cancer group as well as a significant zinc/vitamin A correlation (P = < 0.05). The possible significance of this in relation to the pathogenesis of carcinoma of the prostate is discussed.



Influence of isoflavones in soy protein isolates on development of induced prostate-related cancers in L-W rats

Pollard M.; Luckert P.H.
M. Pollard, Lobund Lab, University of Notre Dame, Notre Dame, IN 46556 USA
Nutrition and Cancer (USA), 1997, 28/1 (41-45)

Lobund-Wistar (L-W) rats are inherently susceptible to spontaneous and induced metastasizing adenocarcinomas in the prostate-seminal vesicle (P-SV) complex. L-W rats were fed soy protein isolates containing high isoflavones (genistein and daidzein) or low isoflavones to determine their effects on development of induced P-SV tumors in two stages of the tumorigenic process. In rats fed the high-isoflavone-supplemented soy diet before initiation by methylnitrosourea (MNU), the incidence of induced prostate-related cancer was reduced and the disease-free period was prolonged by 27% compared with rats fed the same diet but low in isoflavones. Rats fed the same diets, started after MNU, manifested suggestive but less consistent results than those noted above. The incidence rates were of marginal significance, suggesting that the high intensity of the active induced disease may not represent the character of the slower-growing spontaneous (natural) disease. The delay of disease onset is of clinical significance.



Peptide growth factors: Clinical and therapeutic strategies

Di Silverio F.; Sciarra A.; Di Nicola S.; Di Chiro C.
F. Di Silverio, Dipartimento 'U. Bracci', Universita 'La Sapienza', Viale del Policlinico, 00161 Roma Italy
Minerva Urologica e Nefrologica (Italy), 1997, 49/2 (63-72)

The literature contains many accounts of studies in which tumour growth has been accelerated by administration of a particular mitogen and the response then inhibited by co-administration of the corresponding antagonist. Much effort has been focused on the development of cytokine or growth factor antagonists. Like most other cancer therapies, biological therapies will undoubtedly have undesirable toxicities because the proteins they target may not be unique to malignant cells. We received the clinical and therapeutic potential of growth factor agonists and antagonists in some non urologic and urologic diseases. In a recent report we demonstrated that both androgen and antiandrogen treatments enhance the proliferation rate of the hormone-dependent prostate cancer cell line LNCaP, expressing a mutated androgen receptor. Simultaneous treatment with 1 nM R1881 and 100 nM OH-Flutamide, completely counteracted the androgen-induced increase of Epidermal Growth Factor (EGF) levels. Moreover we found that Testosterone, DHT and EGF are mainly concentrated in the periurethral zone in human BPH and long term treatment with Finasteride and with Flutamide modify the distribution and concentration of these factors. Some authors analyzed whether the addition of aurin tricarboxylic acid (ATA) can reduce the growth rate of basic FGF-dependent cells in a manner similar to suramin.



Cancer risk factors for selecting cohorts for large-scale chemoprevention trials

Greenwald P.
Dr. P. Greenwald, Dept. of Health and Human Services, National Institutes of Health, National Cancer Institute, Bethesda, MD 20892 USA
Journal of Cellular Biochemistry (USA), 1996, 63/SUPPL. 25 (29-36)

Many anticipate that application of findings in molecular genetics will help to achieve greater precision in defining high-risk populations that may benefit from chemopreventive interventions. We must recognize, however, that genetic susceptibility, environmental factors, and complex gene-environment interactions are all likely to be risk determinants for most cancers. Cohort studies of twins and cancer indicate that having 'identical' genes is generally not a very accurate predictor of cancer incidence. Data from twin studies support the suggestion that environmental factors such as tobacco use significantly influence cancer risk. The complexities of the genetic contribution to disease risk are exemplified by the development of Duchenne muscular dystrophy in only one of monozygotic twin girls, hypothesized to be the result of X chromosome inactivation, with the distribution patterns of the X chromosome being skewed to the female X in the manifesting twin and to the male X in the normal twin. Evidence from transgenic and genetic- environmental studies in animals support the possibility of genetic- environmental interactions. Calorie restriction modifies tumor expression in p53 knockout mice; a high-fat, low-calcium, low-vitamin D diet increases prepolyphyperplasia formation in Apc-mutated mice; and calorie restriction early in life influences development of obesity in the genetically obese Zucker rat (fata). Such environmental modulation of gene expression suggests that chemoprevention has the potential to reduce risk for both environmentally and genetically determined cancers. In view of the growing research efforts in chemoprevention, the NCl has developed a Prevention Trials Decision Network (PTDN) to formalize the evaluation and approval process for large scale chemoprevention trials. The PTDN addresses large trial prioritization and the associated issues of minority recruitment and retention; identification and validation of biomarkers as intermediate endpoints for cancer; and chemopreventive agent selection and development. A comprehensive database is being established to support the PTDN's decision making process and will help to determine which agents investigated in preclinical and early phase clinical trials should move to large-scale testing. Cohorts for large-scale chemoprevention trials include individuals who are determined to be at high risk as a result of genetic predisposition, carcinogenic exposure, or the presence of biomarkers indicative of increased risk. Current large scale trials in well-defined, high-risk populations include the Breast Cancer Prevention Trial (tamoxifen), the Prostate Cancer Prevention Trial (finasteride), and the N-(4-hydroxyphenyl) retinamide (4- HPR) breast cancer prevention study being conducted in Milan. Biomarker studies will provide valuable information for refining the design and facilitating the implementation of future large-scale trials. For example, potential biomarkers are being assessed at biopsy in women with ductal carcinoma in situ (DCIS). The women are then randomized to either placebo, tamoxifen, 4-HPR, or tamoxifen plus 4-HPR for 2-4 weeks, at which time surgery is performed and the biomarkers reassessed to determine biomarker modulation by the interventions. For prostate cancer, modulation of prostatic intraepithelial neoplasia (PIN) by 4-HPR and difluoromethylornithine is being investigated; similar studies are being planned for oltipraz, dehydroepiandrosterone, and vitamin E plus selenomethionine. The validation of biomarkers as surrogate endpoints for cancer incidence in high-risk cohorts will allow more agents to be evaluated in shorter studies that use fewer subjects to achieve the desired statistical power.



Inhibition of liposomal lipid peroxidation by isoflavonoid type phyto-oestrogens from soybeans of different countries of origin

Wiseman H.; Lim P.; O'Reilly J.
Department Nutrition and Dietetics, King's College London, Campden Hill Road, London W8 7AH United Kingdom
Biochemical Society Transactions (United Kingdom), 1996, 24/3 (392S)

No abstract.



Phytoestrogens: Epidemiology and a possible role in cancer protection

Adlercreutz H.
Department of Clinical Chemistry, University of Helsinki, Meilahti Hospital, FIN-00290 Helsinki Finland
Environmental Health Perspectives (USA), 1995, 103/SUPPL. 7 (103-112)

Because many diseases of the Western Hemisphere are hormone-dependent cancers, we have postulated that the Western diet, compared to a vegetarian or semivegetarian diet, may alter hormone production, metabolism or action at the cellular level by some biochemical mechanisms. Recently, our interest has been mainly focused on the cancer-protective role of some hormonelike diphenolic phytoestrogens of dietary origin, the lignans and the isoflavonoids. The precursors of the biologically active compounds originate in soybean products (mainly isoflavonoids), whole grain cereal food, seeds, and probably berries and nuts (mainly lignans). The plant lignan and isoflavonoid glycosides are converted by intestinal bacteria to hormonelike compounds with weak estrogenic but also antioxidative activity; they have now been shown to influence not only sex hormone metabolism and biological activity but also intracellular enzymes, protein synthesis, growth factor action, malignant cell proliferation, differentiation, and angiogenesis in a way that makes them strong candidates for a role as natural cancer-protective compounds. Epidemiologic investigations strongly support this hypothesis because the highest levels of these compounds in the diet are found in countries or regions with low cancer incidence. This report is a review on recent results suggesting that the diphenolic, isoflavonoids and lignans are natural cancer-protective compounds.



Differential sensitivity of human prostatic cancer cell lines to the effects of protein kinase and phosphatase inhibitors

Rokhlin O.W.; Cohen M.B.
University of Iowa, Department of Pathology, 118 ML, Iowa City, IA 52242 USA
Cancer Letters (Ireland), 1995, 98/1 (103-110)

We investigated the effect of protein kinase and phosphatase inhibitors on the growth of six human prostatic cancer cell lines: DU145, PC3, ND1, LNCaP, ALVA31 and JCA1. We studied okadaic acid and sodium orthovanadate as serine/threonine and tyrosine protein phosphatase inhibitors, respectively, and staurosporin and genistein as a serine/threonine and tyrosine protein kinase inhibitors, respectively. All inhibitors examined exhibited a dose-dependent growth inhibitory effect on prostatic cancer cell lines. Our data indicate that prostatic cancer cell lines express unique biochemical properties since the degree of growth inhibition varied greatly and was dependent on the specific cell line and inhibitor studied. In addition, we found that surface expression of endoglin (CD105) changed by treatment with all inhibitors in most of the cell lines. These data also indicate that endoglin appears to be involved both in protein phosphatase and kinase mediated phosphoprotein turnover.



Genetic damage and the inhibition of 7,12-dimethylbenz(a)anthracene-induced genetic damage by the phytoestrogens, genistein and daidzein, in female ICR mice

Giri A.K.; Lu L.-J.W.
Dept. Prevent. Med. Community Hlth., University of Texas Medical Branch, 700 Strand, Galveston, TX 77555-1110 USA
Cancer Letters (Ireland), 1995, 95/1-2 (125-133)

Populations consuming soybeans have reduced rates of breast, colon and prostate cancer possibly due, in part, to the presence in soybeans of two estrogenic isoflavones, genistein and daidzein. This study investigated the genotoxicity of these soya isoflavones and their interactions with 7,12-dimethylbenz(a)anthracene (DMBA)-induced sister chromatid exchanges (SCE) in bone marrow cells and DNA adduct formations in liver and mammary glands of mice. Groups of female ICR mice were pretreated i.p. with daidzein and/or genistein (10-20 mg/kg per day for 6 days or 50 mg/kg per 12 h for 3 days) or with the solvent, dimethylsulfoxide (DMSO). The mice were implanted with bromodeoxyuridine (BrdU) tablets s.c., and treated with DMBA (50 mg/kg) i.p. and colchicine (4 mg/kg) i.p. 24, 23, and 2 h before sacrifice, respectively. In bone marrow cells, DMBA alone induced 11.73 plus or minus 1.42 SCE/cell compared to 4.35 plus or minus 0.83 SCE/cell in the DMSO treated controls (P = 0.001). DMBA induced 20% fewer SCE (P < 0.05) in mice pretreated with daidzein, genistein or a combination of genistein and daidzein (6 x 20 mg/kg per day for 6 days) when compared to mice that received no pretreatments. Genistein at 50 mg/kg per 12 h for 3 days also inhibited DMBA-induced SCE by 20%. However, treatment for 3 days with 50 mg/kg per 12 h of genistein or daidzein alone, or a combination of daidzein plus genistein (without DMBA treatment) also induced more SCE than treatment with only the solvent (DMSO, P < 0.05). Pretreatment with both the low and the high doses of daidzein plus genistein or the high dose of genistein reduced the replication index of bone marrow cells when compared to pretreatment with DMSO (P < 0.05). Pretreatment with genistein reduced DMBA-induced DNA adduct formation by 34%, but this was only marginally significant (P = 0.08) due to the large inter-individual variability in adduct levels. These results show that genistein and daidzein suppress SCE and possibly DNA adduct formation induced by the known carcinogen, DMBA. This response to a low dose isoflavone exposure may be partly responsible for the protective effect against endocrine cancers of soya consumption.



Rationale for the use of genistein-containing soy matrices in chemoprevention trials for breast and prostate cancer

Barnes S.; Peterson T.G.; Coward L.
Department of Pharmacology, Birmingham Medical Center, University of Alabama, 1670 University Boulevard, Birmingham, AL 35294-0019 USA
Journal of Cellular Biochemistry (USA), 1995, 58/SUPPL. 22 (181-187)

Pharmacologists have realized that tyrosine kinase inhibitors (TKI) have potential as anti-cancer agents, both in prevention and therapy protocols. Nonetheless, concern about the risk of toxicity caused by synthetic TKIs restricted their development as chemoprevention agents. However, a naturally occurring TKI (the isoflavone genistein) in soy was discovered in 1987. The concentration of genistein in most soy food materials ranges from 1-2 mg/g. Oriental populations, who have low rates of breast and prostate cancer, consume 20-80 mg of genistein/day, almost entirely derived from soy, whereas the dietary intake of genistein in the US is only 1-3 mg/day. Chronic use of genistein as a chemopreventive agent has an advantage over synthetic TKIs because it is naturally found in soy foods. It could be delivered either in a purified state as a pill (to high-risk, motivated patient groups), or in the form of soy foods or soy-containing foods. Delivery of genistein in soy foods is more economically viable ($1.50 for a daily dose of 50 mg) than purified material ($5/day) and would require no prior approval by the FDA. Accordingly, investigators at several different sites have begun or are planning chemoprevention trials using a soy beverage product based on SUPRO(TM), an isolated soy protein manufactured by Protein Technologies International of St. Louis, MO. These investigators are examining the effect of the soy beverage on surrogate intermediate endpoint biomarkers (SIEBs) in patients at risk for breast and colon cancer, defining potential SIEBs in patients at risk for prostate cancer, and determining whether the soy beverage reduces the incidence of cancer recurrence. These studies will provide the basis for formal Phase I, Phase II and Phase III clinical trials of genistein and soy food products such as SUPRO(TM) for cancer chemoprevention.



A simplified method to quantify isoflavones in commercial soybean diets and human urine after legume consumption

Lu L.-J.W.; Broemeling L.D.; Marshall M.V.; Ramanujam V.M.S.
Prevent. Med./Community Health Dept., 2.102 Ewing Hall, University of Texas, 700 Strand, Galveston, TX 77555-1110 USA
Cancer Epidemiology Biomarkers and Prevention (USA), 1995, 4/5 (497-503)

Reliable and economical quantification of micronutrients in diets and humans is a critical component of successful epidemiological studies to establish relationships between dietary constituents and chronic disease. Legumes are one of the major dietary components consumed by populations worldwide. Consumption of legumes is thought to play a major role in lowering breast and prostate cancer risk. In this study, a simplified method that uses solid-phase extraction and gas chromatography was developed to measure isoflavones at levels down to 10 microg/5 ml. With the use of this method, 12.5 g miso (a soybean paste), 12 ounces Isomil, and 12 ounces soymilk had daidzin/daidzein levels of 2, 5, and 12.4 mg, respectively, and genistin/genistein levels of 3, 6.5, and 13.7 mg, respectively. In these products, most of the isoflavones were present as glucosides. With the same method, urinary levels of isoflavones in six 15-17-year-old subjects were determined after soymilk ingestion. Each subject was placed on unrestricted nonsoya diets, and three 12-ounce portions of soymilk were given at 12-h intervals. Males excreted 15.02 plus or minus 2.74 (SD) mg of daidzein glucuronides/sulfates (mean recovery, 40.4 plus or minus 7.4% (SD)) by 24 h after the third soymilk ingestion, whereas females excreted 25.56 plus or minus 5.10 mg (68.7 plus or minus 13.7%) of daidzein conjugates, which was more than males (P = 0.02). Males and females excreted 7.73 plus or minus 1.95 mg and 9.11 plus or minus 0.84 mg of genistein glucuronides/sulfates (20% recovery of genistin intake), respectively, in the urine. Most of the isoflavones were excreted within 24 h after ingestion. The relative urinary levels of daidzein to genistein excreted were significantly (P < 0.05) higher in females than males after the third ingestion. The observed sex difference requires more study since two of the females are siblings. Thus, the method described can be used to measure isoflavones in soya products and urinary excretion after soya ingestion.



Rapid HPLC analysis of dietary phytoestrogens from legumes and from human urine

Franke A.A.; Custer L.J.; Cerna C.M.; Narala K.
Molecular Carcinogenesis Program, Cancer Research Center of Hawaii, 1236 Lauhala Street, Honolulu, HI 96813 USA
Proc. Soc. Exp. Biol. Med. (USA), 1995, 208/1 (18-26)

Due to growing evidence suggesting that phytoestrogens might protect against various cancers, particularly against breast and prostate cancer, it is important to measure the exposure of populations to these compounds by determining levels in food and in human tissue or body fluids to assess the possible cancer protective properties of these agents. Therefore, we developed a simple and fast procedure to extract and simultaneously hydrolyze phytoestrogens and their conjugates from food items, and present a fast and selective high-performance liquid chromatography (HPLC) method for precise determinations of the most common dietary phytoestrogens genistein, biochanin-A, daidzein, formononetin, and coumestrol using flavone as internal standard. For the first time HPLC was applied to measure these phytoestrogens and their most abundant metabolites equol and O-desmethyl-angotensin from human urine. The proposed methodology has been evaluated for losses due to thermal degradation during extraction and hydrolysis and due to sample handling during the entire work-up including solid phase extraction, and values are given for inter- and intra-assay variability. We present isoflavonoid levels of most common peas and beans used in 'western' and 'eastern' diets and compare isoflavonoid and coumestrol levels of raw, canned, and cooked foods which can be used in future epidemiological studies. We also determined human urinary levels with our methodology comparing values before and after soybean intake.



Soy intake and cancer risk: A review of the in vitro and in vivo data

Messina M.J.; Persky V.; Setchell K.D.R.; Barnes S.
Epidemiology/Biostatistics Program, School of Public Health, University of Illinois, Chicago, IL 60680 USA
Nutr. Cancer (USA), 1994, 21/2 (113-131)

International variations in cancer rates have been attributed, at least in part, to differences in dietary intake. Recently, it has been suggested that consumption of soyfoods may contribute to the relatively low rates of breast, colon, and prostate cancers in countries such as China and Japan. Soybeans contain a number of anticarcinogens, and a recent National Cancer Institute workshop recommended that the role of soyfoods in cancer prevention be investigated. In this review, the hypothesis that soy intake reduces cancer risk is considered by examining relevant in vitro, animal, and epidemiological data. Soybeans are a unique dietary source of the isoflavone genistein, which possesses weak estrogenic activity and has been shown to act in animal models as an antiestrogen. Genistein is also a specific inhibitor of protein tyrosine kinases; it also inhibits DNA topoisomerases and other critical enzymes involved in signal transduction. In vitro, genistein suppresses the growth of a wide range of cancer cells, with IC50 values ranging from 5 to 40 microM (1-10 microg/ml). Of the 26 animal studies of experimental carcinogenesis in which diets containing soy or soybean isoflavones were employed, 17 (65%) reported protective effects. No studies reported soy intake increased tumor development. The epidemiological data are also inconsistent, although consumption of nonfermented soy products, such as soymilk and tofu, tended to be either protective or not associated with cancer risk; however, no consistent pattern was evident with the fermented soy products, such as miso. Protective effects were observed for both hormone- and nonhormone-related cancers. While a definitive statement that soy reduces cancer risk cannot be made at this time, there is sufficient evidence of a protective effect to warrant continued investigation.



Plasma concentrations of phyto-oestrogens in Japanese men

Adlercreutz H.; Markkanen H.; Watanabe S.
Department of Clinical Chemistry, University of Helsinki, Mellahti Hospital, SF-00290 Helsinki Finland
Lancet (United Kingdom), 1993, 342/8881 (1209-1210)

A low mortality from prostatic cancer is found in Japanese men consuming a low-fat diet with high content of soy products, a rich source of isoflavonoids. We therefore assayed four isoflavonoids in plasma of 14 Japanese and 14 Finnish men. The geometric mean plasma total individual isoflavonoid levels were 7 to 110 times higher in the Japanese than in the Finnish men. Genistein, a tyrosine kinase inhibitor, occurred in the highest concentration (geometric mean 276 nmol/L). We hypothesise that these high phyto-oestrogen levels may inhibit the growth of prostatic cancer in Japanese men, which may explain the low mortality from prostatic cancer in that country.



Genistein is an effective stimulator of sex hormone-binding globulin production in hepatocarcinoma human liver cancer cells and suppresses proliferation of these cells in culture

Mousavi Y.; Adlercreutz H.
Department of Clinical Chemistry, University of Helsinki, Meilahti Hospital, SF-00290 Helsinki Finland
Steroids (USA), 1993, 58/7 (301-304)

Studies have indicated a correlation between a high level of urinary lignans and isoflavonoid phytoestrogens, particularly genistein, and a low incidence of hormone-dependent cancers, such as breast and prostate cancer. Previously it has been observed that a vegetarian diet is associated with high plasma levels of sex hormone-binding globulin (SHBG), reducing clearance of sex hormones and probably risk of breast and prostate cancer. In the present study we investigated the in vitro effect of genistein on the production of SHBG by human hepatocarcinoma (Hep-G2) cells in culture and its effect on cell proliferation. We found that genistein not only highly significantly increases the SHBG production by Hep-G2 cells, but also suppresses the proliferation of these cancer cells already at a stage when SHBG production continues to be high. We conclude that, in addition to the lignan enterolactone, the most abundant urinary isoflavonoid genistein stimulates SHBG production and inhibits Hep-G2 cancer cell proliferation.



Genistein and biochanin A inhibit the growth of human prostate cancer cells but not epidermal growth factor receptor tyrosine autophosphorylation

Peterson G.; Barnes S.
Department of Pharmacology, University of Alabama, Birmingham, AL 35294-0019 USA
Prostate (USA), 1993, 22/4 (335-345)

The effect of the isoflavones, genistein, daidzein, and biochanin A on the growth of the LNCaP and DU-145 human prostate cancer cell lines has been examined. Genistein and biochanin A, but not daidzein, inhibit both serum and EGF-stimulated growth of LNCaP and DU-145 cells (IC50 values from 8.0 to 27 microg/ml for serum and 4.3 to 15 microg/ml for EGF), but have no significant effect of the EGF receptor tyrosine autophosphorylation. In contrast, tyrphostin 25, a specific EGF receptor tyrosine kinase inhibitor, inhibits EGF-stimulated growth and EGF receptor tyrosine autophosphorylation in these whole cells, but does not inhibit serum-stimulated growth. These data suggest that the mechanism of action of genistein and biochanin A does not depend on inhibition of EGF receptor tyrosine autophosphorylation, but on a more distal event in the EGF receptor-mediated signal transduction cascade.



Surrogate endpoint biomarkers for phase II cancer chemoprevention trials

Kelloff G.J.; Boone C.W.; Crowell J.A.; Steele V.E.; Lubet R.; Doody L.A.
Chemoprevention Investigat. Studies, Div. of Cancer Prevention/Control, National Cancer Institute, NIH, Bethesda, MD 20892 USA
J. Cell. Biochem. (USA), 1994, 56/SUPPL. 19 (1-9)

Three critical aspects govern successful Phase II cancer chemoprevention trials - well-characterized agents, suitable cohorts, and reliable intermediate biomarkers for measuring efficacy. Requirements for the agent are experimental or epidemiological data showing chemopreventive efficacy, safety on chronic administration, and a mechanistic rationale for the chemopreventive activity observed. The cohort should be suitable for measuring the chemopreventive activity of the agent and the intermediate biomarkers chosen. Also, many cohorts proposed for Phase II trials are patients with previous cancers or premalignant lesions. For such patients, the trials should be conducted within the context of standard treatment to avoid unusual risks. The criteria for biomarkers are that they fit expected biological mechanisms (i.e., differential expression in normal and high-risk tissue, on or closely linked to the causal pathway for the cancer, modulated by chemopreventive agents, and short latency compared with cancer), may be assayed reliably and quantitatively, measured easily, and correlate to decreased cancer incidence. They must occur in sufficient incidence to allow their biological and statistical evaluation relevant to cancer. Since carcinogenesis is a multipath process, single biomarkers are difficult to validate as surrogate endpoints, as they may appear on only one or a few of the many possible causal pathways. Panels of biomarkers, particularly those representing the range of carcinogenesis pathways, may prove more useful as surrogate endpoints. It is important to avoid relying solely on biomarkers representing isolated events that may or may not be on the causal pathway or otherwise associated with carcinogenesis. These include markers of normal cellular processes that may be increased or expressed during carcinogenesis, but are nonspecific. Chemoprevention trials should be designed to fully evaluate the two or three biomarkers that appear to be the best models of the cancer. Additional biomarkers should be considered only if they can be analyzed efficiently and the sample size allows the more important biomarkers to be evaluated completely. Two types of biomarkers that stand out in regard to their high correlation to cancer and their ability to be quantified are measures of intraepithelial neoplasia and indicators of cellular proliferation. Measurements made by computer-assisted image analysis that are potentially useful as surrogate endpoint biomarkers include nuclear pleomorphism comprising nuclear size, shape (roundness), and texture (DNA distribution patterns); nucleolar size and number of nucleoli/nucleus; DNA ploidy; and proliferation biomarkers such as S-phase fraction, bromodeoxyuridine uptake, Ki-67, and proliferating cell nuclear antigen. Phase II chemoprevention trials are currently in progress or planned that will evaluate these biomarkers. The cohorts include patients scheduled for surgery for ductal carcinoma in situ in breast or early breast cancer, patients with previously resected colon tumors or adenomas, patients with prostatic intraepithelial neoplasia, and patients scheduled for prostate cancer surgery.



The 16-ene vitamin D analogs

Uskokovic M.R.; Studzinski G.P.; Gardner J.P.; Reddy S.G.; Campbell M.J.; Koeffler H.P.
M.R. Uskokovic, Hoffmann-La Roche, Inc., Nutley, NJ 07110 USA
Current Pharmaceutical Design (Netherlands), 1997, 3/1 (99-123)

Numerous 16-ene vitamin D analogs were investigated as potential anticancer agents. Several structural modifications have been uncovered that contribute to the improvement in the stimulation of HL-60 cells differentiation, the inhibition of HL-60 cells proliferation and the reduction of calcemic properties in vivo. They include the introduction of 16-, 22E-, 23E- and 23Z-double bonds, 23-triple bond or 22R-allene, and substitution of C26 and C27-hydrogens with fluorine or methyl groups. The biggest gains have been achieved by combination of the 16-double bond with 23-double or triple bond and 26-trifluoro or 26,27-hexafluoro substitution patterns. Separately, the combination of the 16-double bond with 22R-allene has produced a highly active analog. In respect to modifications in the ring A, the high activities in cell differentiation and inhibition of cell proliferation with significant reduction of calcemic properties were observed in the 1alpha-fluoro, 3-desoxy, and 19-nor series. It was also shown that the lack of the 1alpha-hydroxy group can be overcome by an optimized modification in the ring D and the side chain; 25(OH)-16,23E-diene-26,27-F6D3 is fully active in HL-60 cell differentiation assay with only mimimal effects on the cellular calcium homeostasis.



Signal transduction inhibitors as modifiers of radiation therapy in human prostate carcinoma xenografts

Teicher B.A.; Bump E.A.; Palayoor S.; Northey D.; Coleman C.N.
USA
Radiation Oncology Investigations (USA), 1996, 4/5 (221-230)

Radiation therapy is very useful in the treatment of prostate cancer; however, local treatment failure still occurs in the majority of patients with locally advanced disease. The growth and progression of tumors involve signaling through protein growth factors and small molecules such as arachidonic acid cascade products. In order to develop novel agents to enhance the efficacy of radiation therapy for patients with prostate cancer, the ability of signal transduction inhibitors including (1) the antiandrogen, flutamide; (2) the anti-inflammatory agent, ibuprofen; (3) the growth factor receptor antagonist, suramin; (4) the retinoid, all-trans-retinoic acid; and (5) the calcium pump inhibitor, thapsigargin to enhance the response of the human prostate carcinoma xenografts DU-145 and LN-CaP, was assessed. Flutamide acted as a radiation protector of the androgen independent DU-145 tumor but produced an additive antitumor effect in combination with fractionated radiation therapy in the androgen dependent LNCaP tumor. Administration of suramin or thapsigargin along with radiation therapy provided little or no tumor growth delay compared with radiation therapy alone. Treatment with all-trans-retinoic acid did not alter the response of the DU-145 to radiation therapy but increased the response of LNCaP tumor to radiation therapy. Administration of ibuprofen along with radiation therapy was most effective. The radiation dose modifying factor for ibuprofen in the DU-145 tumor was 1.8 and 1.7 for a 1-week and a 2-week fractionated regimen, respectively. Administration of ibuprofen along with radiation therapy to animals bearing the LNCaP tumor resulted in a 2-fold increase in tumor growth delay compared with radiation therapy alone. Further investigation of inhibitors of the arachidonic acid cascade as radiation modifiers is warranted.



Calcium regulation of androgen receptor expression in the human prostate cancer cell line LNCaP

Gong Y.; Blok L.J.; Perry J.E.; Lindzey J.K.; Tindall D.J.
Department of Urology Research, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905 USA
Endocrinology (USA), 1995, 136/5 (2172-2178)

Elevation of intracellular calcium levels in the presence of normal androgen levels has been implicated in apoptotic prostate cell death. Since the androgen receptor (AR) plays a critical role in the regulation of growth and differentiation of the prostate, it was of interest to determine whether Ca2+ would affect the expression of androgen receptor messenger RNA (mRNA) and protein, thus affecting the ability of androgens to control prostate function. AR-positive human prostate cancer cells, LNCaP, were incubated with either the calcium ionophore A23187 or the intracellular endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin. Subsequently, AR mRNA and protein levels were assessed by Northern and Western blot analysis. Both A23187 and thapsigargin were found to down-regulate steady state AR mRNA levels in a time- and dose-dependent manner. AR mRNA began to decrease after 6-8 h of incubation with 10-6 M A23187 or 10-7 M thapsigargin, reaching a nadir at 16 and 10 h of incubation, respectively. In contrast, control mRNA (glyceraldehyde 3-phosphate dehydrogenase) did not change significantly during the treatments with either A23187 or thapsigargin. AR protein levels were found to be decreased after 12 h of incubation with either 10-6 M A23187 or 10-7 M thapsigargin. The decrease in AR mRNA and protein seemed to precede apoptosis, since neither A23187 (24 h) nor thapsigargin (30 h) was found to alter cell morphology within the treatment time. Cycloheximide and actinomycin D were unable to change the calcium-mediated decrease in AR mRNA, ruling out the necessity for de novo protein synthesis or a change in mRNA stability. Moreover, the decrease in AR mRNA induced by calcium does not seem to involve protein kinase C- or calmodulin-dependent pathways, since inhibitors of these cellular components had no effect. Nuclear run-on assays demonstrated little or no effects of either A23187 or thapsigargin treatment on AR gene transcription (8 h and 10 h). In conclusion, these studies show that intracellular calcium seems to be a potent regulator of AR gene expression in LNCaP cells.



The role of calcium, pH, and cell proliferation in the programmed (apoptotic) death of androgen-independent prostatic cancer cells induced by thapsigarin

Furuya Y.; Lundmo P.; Short A.D.; Gill D.L.; Isaacs J.T.
Johns Hopkins Oncology Center, 422 N. Bond Street, Baltimore, MD 21231 USA
Cancer Res. (USA), 1994, 54/23 (6167-6175)

Calcium (Ca2+) accumulates within the endoplasmic reticulum of cells through function of the sarcoplasmic reticulum and endoplasmic reticulum Ca2+-dependent ATPase family of intracellular Ca2+-pumping ATPases. The resulting pools have important signaling functions. Thapsigargin (TG) is a sesquiterpene gamma-lactone which selectively inhibits the sarcoplasmic reticulum and endoplasmic reticulum Ca2+-dependent ATPase pumps with a 50% inhibitory concentration of approximately 30 microM. Treatment of androgen- independent prostate cancer cells of both rat and human origin with TG inhibits their endoplasmic reticulum Ca2+-dependent ATPase activity, resulting in a 3-4-fold elevation in the level of intracellular free Ca2+ (Ca(i)) within minutes of exposure. Due to a secondary influx of extracellular Ca2+, this increase in Ca(i) is sustained, resulting in morphological (cell rounding) and biochemical changes within 6-12 h (enhanced calmodulin, glucose regulated protein, and tissue transglutaminase expression, and decreased expression of the G(i) cyclins). Within 24 h of exposure, androgen-independent prostatic cancer cells stop progression through the cell cycle, arrest out of cycle in G0, and irreversibly lose their ability to proliferate with a median effective concentration value of 31 nM TG. During the next 24-48 h, the genomic DNA of the G0-arrested cells undergoes double-strand fragmentation. This is followed by the loss of plasma membrane integrity and fragmentation of the cell into apoptotic bodies. During this process, there is no acidification in the intracellular pH. Using cells transfected with the avian M(r) 28,000 calbindin D Ca2+-buffering protein, it was demonstrated that the programmed death initiated by TG is critically dependent upon an adequate (i.e., 3-4-fold) sustained (>1 h) elevation in Ca(i) and not depletion of the endoplasmic reticulum pools of Ca2+. These results demonstrate that TG induces programmed cell in androgen-independent prostatic cancer cells in a dose-dependent manner and that this death does not require proliferation or intracellular acidification but is critically dependent upon an adequate, sustained (i.e., >1 h) elevation in Ca(i).



Programmed cell death as a new target for prostatic cancer therapy

Kyprianou N.; Martikainen P.; Davis L.; English H.F.; Isaacs J.T.
Johns Hopkins Oncology Center, Baltimore, MD 21205 USA
Cancer Surv. (USA), 1991, 11/- (265-277)

To increase survival of men with metastatic prostatic cancer, a modality that can effectively eliminate androgen independent cancer cells is desperately needed. By combining such an effective modality with androgen ablation, all of the heterogeneous populations of tumour cells within a prostatic cancer patient can be affected, thus optimizing the chances of cure. Unfortunately, such effective therapy for the androgen independent prostatic cancer cell is not yet available. This therapy will probably require two types of agents, one having antiproliferative activity affecting the small number of dividing androgen independent cells, and the other able to increase the low rate of cell death among the majority of non- proliferating (ie interphase) androgen independent prostatic cancer cells present. Androgen dependent prostatic epithelial cells can be made to undergo programmed death by means of androgen ablation, even if the cells are not in the proliferative cell cycle. Androgen independent prostatic cancer cells retain the major portion of this programmed cell death pathway, only there is a defect in the pathway such that it is no longer activated by androgen ablation. If the intracellular free Ca2+ is sustained at an elevated level for a sufficient time, androgen independent cells can be induced to undergo programmed death. The long term goal is therefore to develop some type of non-androgen ablative method that can be used in vivo to induce a sustained elevation in Ca2+ in androgen independent prostatic cancer cells. To accomplish this task, a more complete understanding of the biochemical pathways involved in programmed cell death is urgently needed. At present, studies are focusing on the mechanism involved in the Ca2+ elevation in the normal and malignant androgen dependent cell induced following androgen ablation and the role of the TRPM-2 protein in this process.



Hyperparathyroidism in metastases of prostatic carcinoma: A biochemical, hormonal and histomorphometric study

Rico H.; Uson A.; Hernandez E.R.; Prados P.; Paramo P.; Cabranes J.A.
Department of Medicine, Medical School, University of Alcala de Henares, E-28871 Madrid Spain
Eur. Urol. (Switzerland), 1990, 17/1 (35-39)

Secondary hyperparathyroidism can develop as a result of bone metastases from prostatic cancer, but this has not been studied from the multiple aspects of biochemistry, hormonal status and histomorphometry. In 20 patients with stage-D prostatic cancer, a transiliac bone biopsy was performed for histomorphometric study. In all of them, molecular parathormone (PTH-M) and osteocalcin were determined by radioimmunoassay together with other parameters considered to be biological markers of bone remodelling. Of these 20 patients, only 2 (10%) had elevated PTH-M (240 plus or minus 20.6 pmol/l), differing significantly from the other 18 (58.6 plus or minus 11.7 pmol/l) and from controls (60.4 plus or minus 7.2 pmol/l). In the high PTH-M patients, corrected calcium was low (7.8 plus or minus 0.4 mg/dl) as compared to normal PTH-M patients (9.2 plus or minus 0.5 mg/dl, p < 0.001), and this was also the case for serum phosphorus (2.2 plus or minus 0.6 vs. 3.2 plus or minus 0.3 and 3.4 plus or minus 0.4 mg/dl, respectively p < 0.001). Alkaline phosphatase was raised in the patient groups as compared to controls (p < 0.001) and was higher in the high PTH-M group (362 plus or minus 58 vs. 224 plus or minus 62 U/l, p < 0.001). The same pattern of higher values in the hyperparathyroid patients was repeated for: hydroxyproline/Cr in fasting urine (3.6 plus or minus 0.2 vs. 2.1 plus or minus 0.4 mg/mg, p < 0.001); Ca/Cr in fasting urine (0.08 plus or minus 0.02 vs. 0.007 plus or minus 0.01 mg/mg, p < 0.001, decreased in both patient groups but more so in the high PTH-M group), and for the 24-hour urinary calcium (128 plus or minus 22 vs. 86 plus or minus 11 mg, p < 0.001) which was only reduced (p < 0.001) in normals. Serum osteocalcin, although raised in both groups, did not differ significantly between patient groups (15.1 plus or minus 2.3 ng/ml for hyperparathyroid patients and 14.4 plus or minus 5.2 ng/ml for normals), but was significantly different between patients and controls (6.8 plus or minus 3.1 ng/ml, p < 0.001). Histomorphometrically, trabecular bone volume was elevated in both groups as compared to controls (p < 0.001), and the resorption surface was increased in hyperparathyroid patients (9.7 plus or minus 1.1 vs. 4.7 plus or minus 2.8%, p < 0.001), as was the osteoid seam thickness index (31.8 plus or minus 6.2 vs. 18.6 plus or minus 5.6, p < 0.001). According to the Pearson test, only effected in the normoparathyroid group, the only significant and positive correlations were between osteocalcin and 24-hour urine calcium and between osteocalcin and Ca/Cr (both p < 0.001). These results demonstrate the existence of a secondary hyperparathyroidism in 10% of patients with blastic bone metastases due to stage-D prostatic cancer and show that osteocalcin is not an adequate biological bone marker in these patients.



In vitro studies of human prostatic epithelial cells: Attempts to identify distinguishing features of malignant cells

Peehl D.M.; Wong S.T.; Bazinet M.; Stamey T.A.
Division of Urology, Stanford Medical Center, Stanford, CA 94305 USA
Growth Factors (United Kingdom), 1989, 1/3 (237-250)

Recent advances in culture techniques have enabled routine establishment and propagation of epithelial cells derived from normal and malignant tissues of the human prostate. Comparative studies of the responses of normal and cancer-derived cell populations to various growth and differentiation factors in vitro were undertaken to examine the possibility that cancer cells might respond differentially. Clonal growth assays in serum-free medium demonstrated that optimal proliferation of normal as well as cancer cell strains was generally dependent on the presence of cholera toxin, epidermal growth factor, pituitary extract, hydrocortisone, insulin and high levels of calcium in the culture medium, and on the use of collagen-coated dishes. Only one cancer strain responded aberrantly to epidermal growth factor and hydrocortisone. Putative differentiation factors (transforming growth factor-beta and vitamin A) inhibited the growth of all normal and cancer strains. The origin of a cancer-derived cell strain that responded similarly to normal strains was verified by positive labeling with a prostate cancer-specific antibody, validating the conclusion from these studies that normal and cancer prostatic epithelial cells are not distinguishable on the basis of responses to the tested factors.



Hypocalcemia associated with estrogen therapy for metastatic adenocarcinoma of the prostate

Vogelgesang S.A.; McMillin J.M.
Research Service, Sioux Falls Veterans Administration Hospital, Sioux Falls, SD USA
J. Urol. (USA), 1988, 140/5 Part I (1025-1027)

We report 2 cases of true hypocalcemia (not caused by decreased binding protein) associated with metastatic prostate cancer and review previously reported cases. Hypocalcemia is a common but frequently unrecognized complication of prostatic cancer. Estrogen therapy often is associated with the hypocalcemia, which may be asymptomatic. The hypocalcemia is always associated with osteoblastic metastases and usually it is associated with increased serum alkaline phosphatase activity, acid phosphatase activity and serum parathyroid hormone concentration. Serum concentrations of magnesium, phosphorus and vitamin D frequently are decreased. Patients are in a positive calcium balance. The osteoblastic metastases seem to act as a calcium sink, creating a 'hungry tumor phenomenon'. The role of estrogens may be to stop the resorption of normal bone resulting in lower serum calcium concentrations.



Hypercalcemia in carcinoma of the prostate: Case report and review of the literature

George A.L. Jr.; Remler R.B.; Heim C.R.; Warner J.J.
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN USA
J. Urol. (Baltimore) (USA), 1987, 137/2 (309-311)

Hypercalcemia developed in a man with recurrent adenocarcinoma of the prostate. Serum calcium became normal soon after bilateral orchiectomy and the patient was free of disease 18 months later. The absence of radiographically detectable bone metastases in this patient suggested a humoral mechanism for the hypercalcemia. Orchiectomy may be an effective treatment for hypercalcemia complicating prostatic carcinoma.



Calcium excretion in metastatic prostatic carcinoma

Grainger R.; Reda M.; Fitzpatrick J.M.
Department of Urology, Meath Hospital, Dublin 8 Ireland
Br. J. Urol. (England), 1984, 56/6 (687-689)

In 64 men with prostatic carcinoma, calcium excretion per litre of glomerular filtrate (Ca(e)) was persistently lower in those with bone secondaries than in those with soft tissue involvement only, despite a normal range of serum calcium in both groups. In three patients who showed an improvement in their bony metastases on bone scan 6 months after starting treatment, the Ca(e) values had increased slightly but still remained in the low range. In a further five who showed no improvement on bone scan, Ca(e) values were lower than before. In patients with prostatic carcinoma, Ca(e) is an indicator of early changes in calcium homeostasis. It may also provide an objective indication of progression of bone secondaries.



Osteomalacia associated with prostatic cancer and osteoblastic metastases

Kabadi U.M.
Dep. Med., Veterans Adm. Med. Cent., Des Moines, IA 50310 USA
Urology (USA), 1983, 21/1 (65-67)

A patient with carcinoma of the prostate, extensive bony metastases, and osteomalacia is reported. The diagnosis of osteomalacia was suspected because of generalized weakness and bone pains, hypocalcemia, hypophosphatemia, and raised alkaline phosphatase. It was documented by low 1,25-hydroxyvitamin D level. Furthermore, it was confirmed by improvement in patient's symptomatology and normalization of serum calcium and phosphorus after treatment with 1,25-hydroxyvitamin Dsub 3 (Rocaltrol).



Carcinoma of the prostate: The treatment of bone metastases by radiophosphorus

Glaser M.G.; Howard N.; Waterfall N.
Dept. Radiother., Charing Cross Hosp., London United Kingdom
Clin. Radiol. (Scotland), 1981, 32/6 (695-697)

Osseous deposits secondary to advanced carcinoma of the prostate are a common feature of the disease. These deposits are most often seen in the lumbar spine and pelvis and cause severe and intractable pain, often requiring large quantities of strong analgesia for alleviation of pain. Relief of pain can be achieved by external irradiation of these deposits, but this relief may not be permanent and the disease may be so widespread that it is impracticable to treat all the deposits by irradiation. Deposits from carcinoma of the prostate are usually multiple and all may cause pain at the same time. A method of delivering the radiation to all the deposits at the same time has been sought. Previous studies have shown that radioactive phosphorus (P32) can be used to obtain this localisation of radioactivity at sites of osseous activity. In this study 24 patients with bone metastases from carcinoma of the prostate were treated with radiophosphorus and methyl testosterone, or radiophosphorus with parathormone and calcium. An overall response rate of 58% shows this to be an effective palliative treatment. The results suggest there is a greater response when P32 is used in conjunction with parathormone and calcium, than with methyl testosterone.



Management of cancer of the prostate

Blackard C.E.
VA Hosp., Minneapolis, Minn. USA
Brit.J.Hosp.Med. (England), 1974, 11/3 (357-372)

In this article the management of prostatic cancer is discussed according to the clinical stage of the tumor. Ordinarily, treatment of prostatic cancer should not be started until a positive histological diagnosis has been made and the patient has been properly staged. Minimal staging studies include a pretreatment prostatic serum acid phosphatase test and a skeletal survey.



Intracavitary irradiation of prostate carcinomas

Dragon V.; Pache G.; Von Niederhausern W.; et al.
Serv. Radiother., CHU Vaudois, Lausanne Switzerland
Rev. Med. Suisse Romande (Switzerland) , 1980, 100/9 (755-762)

A method for the intracavitary irradiation of prostate carcinomas, used at the Central University Hospital in Lausanne in 1979 and 1980 on 10 patients is described. The technique, which is the afterloading type, consists of the positioning of a Cs 137 source in the proximal ureter. This is achieved with the aid of a Foley 26 balloon catheter introduced into the bladder after drainage cystostomy. The source remains in place for about 26 hours and delivers a dose of approximately 3800 rads to the prostate to a depth of 4 cm (NSD=2000 ret) and a maximum of 1700 rads to the rectum (NSD=700 ret).



Epidemiology of prostatic cancer: A case-control study

Fincham S.M.; Hill G.B.; Hanson J.; Wijayasinghe C.
Division of Epidemiology and Preventive Oncology, 6th Floor, 9707-110 Street, Edmonton, Alta. T5K 2L9 Canada
Prostate (USA), 1990, 17/3 (189-206)

A population-based case-control study of prostatic cancer in Alberta was undertaken to determine the risk factors associated with the disease. Cases were 382 newly diagnosed prostatic cancer patients and 625 controls, group-matched to the anticipated age distribution of the cases, chosen at random from the health insurance roster. Subjects were interviewed in their homes by using a pre-tested questionnaire including questions related to ethnic group, education, puberty, marital history, family history, residence, water supply, smoking, and diet. Factors significantly related to the risk of developing prostatic cancer included ethnic group (British high, Ukrainian low), education (elementary high, university low), age at first marriage (early high, late low), family history (high risk for those with relatives with prostatic cancer), and increased masculinity among the children of cases. The results with respect to smoking, occupation, medical history, birthplace, residence, water supply, and diet were generally negative.



Demonstration of specifically sensitized lymphocytes in patients treated with an aqueous mistletoe extract (Viscum album L.)

Schultze J.L.; Stettin A.; Berg P.A.
Medizinische Klinik, Abteilung II, Universitat Tubingen, W-7400 Tubingen Germany
Klin. Wochenschr. (Germany), 1991, 69/9 (397-403)

Lymphocytes of 25 patients treated with an aqueous mistletoe extract (Viscum album L.) for up to 6 months (group 1), up to 2 years (group 2), and more than 2 years (group 3) were examined in 3- and 7-day cultures for specifically sensitized lymphocytes. The whole extract (HM), the lectin-polysaccharide fraction (HM-LP), and the 'viscotoxin' fraction (HM-V) were added at concentrations ranging from 0.5 microg to 12.5 mg extract/ml. Lymphocytes from four of the nine group 2 patients and five of the ten group 3 patients reacted specifically with HM and HM-LP at an optimal dose of 5.0 mg/ml, but did not react with HM-V. Stimulation indices varied between 1.6 and 16. In the patients of group 3 this effect was observed only when their lymphocytes were costimulated in the 3-day cultures with phytohemagglutinin (PHA), in contrast to the four patients of group 2 who reacted only in the 7-day cultures with HM-LP without PHA co-stimulation. Patients' lymphocytes had to be protected from mistletoe lectin-induced cytotoxicity by the addition of their own sera containing anti-mistletoe lectin antibodies. Lymphocytes from tumor patients (n = 18) never treated with mistletoe extracts and healthy individuals (n = 18) showed no specific proliferative response when tested in 3- and 7-day cultures. The production of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-gamma (IFN-gamma) was measured in the supernatants of lymphocytes cultures from all 25 patients and 36 controls exposed to HM, HM-LP, and HM-V in 3- and 7-day cultures.



An urodynamic study of patients with benign prostatic hypertrophy treated conservatively with phytotherapy or testosterone

Flamm J.; Kiesswetter H.; Englisch M.
Urol. Abt., Wilhelminenspit., Wien Austria
Wien. Klin. Wochenschr. (Austria), 1979, 91/18 (622-627)

Conservative therapy of benign prostatic hypertrophy comprises the administration of oestrogens, gestagens, androgens and anti-androgens. Phytodrugs, which contain an extract of Sabal serrulatum or Pygeum Africana as active substance are without side effects and are, therefore, being used increasingly. 74 patients with irritable or obstructive bladder symptoms due to benign prostatic hypertrophy were treated with a phytodrug (Sabal serrulatum) or with testosterone throughout a period of three months. In group one (20 patients given phytodrugs and 10 patients given testosterone) clinical symptoms and measurements of residual urine, residual urine quotient, bladder capacity, micturition pressure and maximum urethral closure pressure were recorded at the beginning and at the end of therapy. In group two 28 patients were treated with the phytodrug in the first and third months with an intervening placebo trial lasting four weeks and 16 patients were given testosterone. Clinical symptoms and uroflow and residual urine only were charted in this group. None of the patients in either group showed an improvement in the urodynamic parameters of obstruction, but all patients felt a subjective alleviation of their symptoms.