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Cancer Radiation Therapy
Updated: 08/26/2004

ABSTRACTS

Genistein, a tyrosine kinase inhibitor, enhanced radiosensitivity in human esophageal cancer cell lines in vitro: possible involvement of inhibition of survival signal transduction pathways.

Akimoto T, Nonaka T, Ishikawa H, et al.

Int J Radiat Oncol Biol Phys. 2001 May 1; 50(1):195-201.

PURPOSE: The effect of genistein, a tyrosine kinase inhibitor, on radiosensitivity was examined, especially focusing on "survival signal transduction pathways." METHODS AND MATERIALS: Two human esophageal squamous cell cancer cell lines, TE-1 (p53, mutant) and TE-2 (p53, wild), were used. Radiosensitivity was determined by clonogenic assay, and activation of survival signals was examined by Western blot. RESULTS: Genistein (30 microM) greatly enhanced radiosensitivity in these cell lines by suppressing radiation-induced activation of survival signals, p42/p44 extracellular signal-regulated kinase and AKT/PKB. Significant increase in the percentage of apoptotic cells and increased poly[ADP-ribose] polymerase cleavage were observed in TE-2, but not in TE-1 even after combination of genistein with irradiation. In terms of changes in expression of p53-related proteins, increase in expression of Bax and decrease in that of Bcl-2 were observed in TE-2 but not in TE-1, suggesting that the main mode of cell death induced by genistein in a cell line with wild type p53 differed from that with mutant p53. CONCLUSIONS: This study suggested that survival signals, including p42/p44 ERK and AKT/PKB, may be involved in determining radiosensitivity, and genistein would be a potent therapeutic agent that has an enhancing effect on radiation

Induction by carbon-ion irradiation of the expression of vascular endothelial growth factor in lung carcinoma cells.

Ando S, Nojima K, Ishihara H, et al.

Int J Radiat Biol. 2000 Aug; 76(8):1121-7.

PURPOSE: To investigate the induction by carbon- ion irradiation of vascular endothelial growth factor (VEGF) mRNA and protein. MATERIALS AND METHODS: RERF-LC-AI lung squamous carcinoma cells were irradiated with carbon ions of either 13.3, 50 or 90keV/microm. Colony formation was used to determine cell survival. VEGF mRNA and protein of the irradiated cells were quantified by Northern blot analysis and ELISA assay, respectively. Genistein, Src tyrosine kinase inhibitor and H7, protein kinase C inhibitor, were used to inhibit VEGF mRNA expression. RESULTS: The relative biological effectiveness (RBE) of carbon ions (13.3, 50 and 90keV/microm) was 1.10, 1.97 and 2.30, respectively, in terms of D10 values. Single doses of 15 Gy with either X-rays or carbon ions significantly induced VEGF mRNA expression at 16-24h after irradiation with a maximum induction of 2.81-fold. A significant increase was also observed in VEGF protein levels, detected in culture supernatant 24h after irradiation with 50 and 90keV/microm carbon ions. Neither mRNA nor protein induction showed a dependence on LET. The induction of VEGF mRNA by carbon-ion irradiation was completely inhibited by pretreating cells with genistein and H7, indicating that Src tyrosine kinase and protein kinase C on cell surface membranes is involved in the induction. CONCLUSION: Irradiation of lung carcinoma cells with carbon ions induced VEGF mRNA expression and increased protein levels. The induction was dose-dependent. Radiation-induced DNA damage and/or its repair may not be a prerequisite for the induction of VEGF mRNA

Nutritional and High Dose Antioxidant Interventions during Radiation Therapy for Cancer of the Breast.

Anon.

7777;October 3-5, 2002a (unpublished)

Role of Vitamins Along with Chemotherapy in Non Small Cell Lung Cancer.

Anon.

7777;October 3-5, 2002b (unpublished).

[Anemia in cancer patients before treatment].

Auclerc G, Meric JB, Pommeyrol A, et al.

Bull Cancer. 2003 Apr; 90 Spec No:S128-S132.

Thirty per cent of cancer patients suffer from anemia before any treatment. This anemia is caused by haematopoiesis troubles related to cytokines production and by endogenous erythropoietin deficiency. Clinically, its symptoms, including fatigue, spoils patients'quality of life. Known as a prognostic factor for several cancers, anemia also lowers radiotherapy or chemotherapy efficiency by tumor hypoxia. Recombinant EPO restores normal haemoglobin level, quality of life and treatment efficiency

Detrimental effect of cancer preventive phytochemicals silymarin, genistein and epigallocatechin 3-gallate on epigenetic events in human prostate carcinoma DU145 cells.

Bhatia N, Agarwal R.

Prostate. 2001 Feb 1; 46(2):98-107.

BACKGROUND: Targeting epigenetic events associated with autonomous growth of advanced prostate cancer (PCA) is a practical approach for its control, prevention, and treatment. Recently we showed that treatment of prostate carcinoma DU145 cells with cancer preventive flavonoid silymarin at 100-200 microM doses inhibits erbB1-Shc mitogenic signaling and modulates cell cycle regulators leading to a G1 arrest and inhibition of cell growth and anchorage-independent colony formation. Here, we asked the question whether these important findings could be extended to other cancer preventive flavonoids and isoflavones such as epigallocatechin 3-gallate (EGCG) and genistein. METHODS: DU145 cells were treated with similar doses (100-200 microM) of silymarin, genistein or EGCG, cell lysates prepared, and levels of activated signaling molecules (erbB1-Shc-ERK1/2) and cell cycle regulators (CDKIs, CDKs, and cyclins) analyzed employing immunoprecipitation and/or immunoblotting techniques. Cell growth studies were done by cell counting during 5 days of treatment with these agents, and cell death was determined by Trypan blue staining. RESULTS: Treatment of cells with silymarin, genistein or EGCG at 100-200 microM resulted in a complete inhibition of TGFalpha-caused activation of erbB1 followed by a moderate to strong inhibition (10-90%) of Shc activation without an alteration in their protein levels. Silymarin and genistein, but not EGCG, also inhibited (10% to complete) ERK1/2 activation suggesting that these agents impair erbB1-Shc-ERK1/2 signaling in DU145 cells. In other studies, silymarin, genistein or EGCG caused a strong induction of Cip1/p21 (up to 2.4-fold) and Kip1/p27 (up to 150-fold), and a strong decrease in CDK4 (40-90%) but had moderate effect on CDK2, and cyclins D1 and E. An enhanced level of CDKIs also led to an increase in their binding to CDK4 and CDK2. Treatment of cells with silymarin, genistein or EGCG also resulted in 50-80% cell growth inhibition at lower doses, and complete inhibition at higher doses. In contrast to silymarin, higher doses of genistein showed cytotoxic effect causing 30-40% cell death. A more profound cytotoxic effect was observed with EGCG accounting for 50% cell death at lower doses and complete loss of viability at higher doses. CONCLUSIONS: These results suggest that similar to silymarin, genistein and EGCG also inhibit mitogenic signaling pathway(s) and alter cell cycle regulators, albeit at different levels, leading to growth inhibition and death of advanced and androgen-independent prostate carcinoma cells. More studies are, therefore, needed with these agents to explore their anti-carcinogenic potential against human prostate cancer

Caffeine inhibits the checkpoint kinase ATM.

Blasina A, Price BD, Turenne GA, et al.

Curr Biol. 1999 Oct 7; 9(19):1135-8.

The basis of many anti-cancer therapies is the use of genotoxic agents that damage DNA and thus kill dividing cells. Agents that cause cells to override the DNA-damage checkpoint are predicted to sensitize cells to killing by genotoxic agents. They have therefore been sought as adjuncts in radiation therapy and chemotherapy. One such compound, caffeine, uncouples cell-cycle progression from the replication and repair of DNA [1] [2]. Caffeine therefore servers as a model compound in establishing the principle that agents that override DNA-damage checkpoints can be used to sensitize cells to the killing effects of genotoxic drugs [3]. But despite more than 20 years of use, the molecular mechanisms by which caffeine affects the cell cycle and checkpoint responses have not been identified. We investigated the effects of caffeine on the G2/M DNA-damage checkpoint in human cells. We report that the radiation-induced activation of the kinase Cds1 [4] (also known as Chk2 [5]) is inhibited by caffeine in vivo and that ATM kinase activity is directly inhibited by caffeine in vitro. Inhibition of ATM provides a molecular explanation of the attenuation of DNA-damage checkpoint responses and for the increased radiosensitivity of caffeine-treated cells [6] [7] [8]

Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy.

Blask DE, Sauer LA, Dauchy RT.

Curr Top Med Chem. 2002 Feb; 2(2):113-32.

Melatonin, as a new member of an expanding group of regulatory factors that control cell proliferation and loss, is the only known chronobiotic, hormonal regulator of neoplastic cell growth. At physiological circulating concentrations, this indoleamine is cytostatic and inhibits cancer cell proliferation in vitro via specific cell cycle effects. At pharmacological concentrations, melatonin exhibits cytotoxic activity in cancer cells. At both physiological and pharmacological concentrations, melatonin acts as a differentiating agent in some cancer cells and lowers their invasive and metastatic status through alterations in adhesion molecules and maintenance of gap junctional intercellular communication. In other cancer cell types, melatonin, either alone or in combination with other agents, induces apoptotic cell death. Biochemical and molecular mechanisms of melatonin's oncostatic action may include regulation of estrogen receptor expression and transactivation, calcium/calmodulin activity, protein kinase C activity, cytoskeletal architecture and function, intracellular redox status, melatonin receptor-mediated signal transduction cascades, and fatty acid transport and metabolism. A major mechanism mediating melatonin's circadian stage-dependent tumor growth inhibitory action is the suppression of epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) activity. This occurs via melatonin receptor-mediated blockade of tumor linoleic acid uptake and its conversion to 13-hydroxyoctadecadienoic acid (13-HODE) which normally activates EGFR/MAPK mitogenic signaling. This represents a potentially unifying model for the chronobiological inhibitory regulation of cancer growth by melatonin in the maintenance of the host/cancer balance. It also provides the first biological explanation of melatonin-induced enhancement of the efficacy and reduced toxicity of chemo- and radiotherapy in cancer patients

Whey protein concentrate (WPC) and glutathione modulation in cancer treatment.

Bounous G.

Anticancer Res. 2000 Nov; 20(6C):4785-92.

The glutathione (GSH) antioxidant system is foremost among the cellular protective mechanisms. Depletion of this small molecule is a common consequence of increased formation of reactive oxygen species during increased cellular activities. This phenomenon can occur in the lymphocytes during the development of the immune response and in the muscular cells during strenuous exercise. It is not surprising that so much research has been done, and is still being done on this small tripeptide molecule. Whey protein concentrate has been shown to represent an effective and safe cysteine donor for GSH replenishment during GSH depletion in immune deficiency states. Cysteine is the crucial limiting amino acid for intracellular GSH synthesis. Animal experiments showed that the concentrates of whey proteins also exhibit anti-carcinogenesis and anticancer activity. They do this via their effect on increasing GSH concentration in relevant tissues, and may have anti-tumor effect on low volume of tumor via stimulation of immunity through the GSH pathway. It is considered that oxygen radical generation is frequently a critical step in carcinogenesis, hence the effect of GSH on free radicals as well as carcinogen detoxification, could be important in inhibiting carcinogenesis induced by a number of different mechanisms. Case reports are presented which strongly suggest an anti-tumor effect of a whey protein dietary supplement in some urogenital cancers. This non toxic dietary intervention, which is not based on the principles of current cancer chemotherapy, will hopefully attract the attention of laboratory and clinical oncologists

Correlation between antioxidant status, tumorigenicity and radiosensitivity in sister rat cell lines.

Bravard A, Ageron-Blanc A, Alvarez S, et al.

Carcinogenesis. 2002 May; 23(5):705-11.

Tumorigenicity and radiosensitivity of related cell lines expressing distinct p53 mutants were analyzed in parallel with key components of the antioxidant metabolic pathway. Six sublines deriving from the same parental cell population and expressing either the mutant p53K130R or p53V270F were investigated. Both mutations abrogate the transcriptional activity of p53 as well as its ability to induce apoptosis. The cells expressing p53K130R showed a higher tumorigenicity and a higher radiosensitivity than those expressing p53V270F. An increase in tumorigenicity was associated with a decrease in manganese-containing superoxide dismutase activity, and with further decreases in the glutathione content and glutathione peroxidase (GPX) activity. A positive correlation was found between GPX activity, glutathione content and cell survival following ionizing irradiation. The fact that sister cell lines exhibit different tumorigenicity and radiosensitivity while expressing a mutant p53 further supports the notion that knowledge of p53 status is not sufficient to predict tumor outcome, especially the response to irradiation. A better understanding of antioxidant defenses might be more informative

Effect of alkoxyglycerols on the frequency of injuries following radiation therapy for carcinoma of the uterine cervix.

Brohult A, Brohult J, Brohult S, et al.

Acta Obstet Gynecol Scand. 1977; 56(4):441-8.

The incidence of injuries following intracavitary and external radiation therapy is markedly decreased in all stages of the disease by the administration of alkoxyglycerols. Complex injuries (due to radiation injury and tumour growth in combination) were reduced to about 1/3 in a group receiving alkoxyglycerols prophylactically, i.e. before, during and after radiation treatment, when compared with a control group. Using non-prophylactic administration of alkoxyglycerols, i.e. during and after radiation treatment, no effect was observed on complex injuries, while--as for the prophylactic group--the injuries due to radiation only, were significantly decreased. The use of so called "increased amount" of radium in the intracavitary irradiator was followed by an unexpectedly high incidence of radiation injuries, which was considerably reduced, however, by alkoxyglycerols, especially when administered prophylactically

Selenium, selenoproteins and human health: a review.

Brown KM, Arthur JR.

Public Health Nutr. 2001 Apr; 4(2B):593-9.

Selenium is of fundamental importance to human health. It is an essential component of several major metabolic pathways, including thyroid hormone metabolism, antioxidant defence systems, and immune function. The decline in blood selenium concentration in the UK and other European Union countries has therefore several potential public health implications, particularly in relation to the chronic disease prevalence of the Western world such as cancer and cardiovascular disease. Ten years have elapsed since recommended dietary intakes of selenium were introduced on the basis of blood glutathione peroxidase activity. Since then 30 new selenoproteins have been identified, of which 15 have been purified to allow characterisation of their biological function. The long term health implications in relation to declining selenium intakes have not yet been thoroughly examined, yet the implicit importance of selenium to human health is recognised universally. Selenium is incorporated as selenocysteine at the active site of a wide range of selenoproteins. The four glutathione peroxidase enzymes (classical GPx1, gastrointestinal GPx2, plasma GPx3, phospholipid hydroperoxide GPx4)) which represent a major class of functionally important selenoproteins, were the first to be characterised. Thioredoxin reductase (TR) is a recently identified seleno-cysteine containing enzyme which catalyzes the NADPH dependent reduction of thioredoxin and therefore plays a regulatory role in its metabolic activity. Approximately 60% of Se in plasma is incorporated in selenoprotein P which contains 10 Se atoms per molecule as selenocysteine, and may serve as a transport protein for Se. However, selenoprotein-P is also expressed in many tissues which suggests that although it may facilitate whole body Se distribution, this may not be its sole function. A second major class of selenoproteins are the iodothyronine deiodinase enzymes which catalyse the 5'5-mono-deiodination of the prohormone thyroxine (T4) to the active thyroid hormone 3,3'5-triiodothyronine (T3). Sperm capsule selenoprotein is localised in the mid-peice portion of spermatozoa where it stabilises the integrity of the sperm flagella. Se intake effects tissue concentrations of selenoprotein W which is reported to be necessary for muscle metabolism. It is of great concern that the health implications of the decline in Se status in the UK over the past two decades have not been systematically investigated. It is well recognised that dietary selenium is important for a healthy immune response. There is also evidence that Se has a protective effect against some forms of cancer; that it may enhance male fertility; decrease cardiovascular disease mortality, and regulate the inflammatory mediators in asthma. The potential influence of Se on these chronic diseases within the European population are important considerations when assessing Se requirement

Prospects of the clinical utilization of melatonin.

Bubenik GA, Blask DE, Brown GM, et al.

Biol Signals Recept. 1998 Jul; 7(4):195-219.

This review summarizes the present knowledge on melatonin in several areas on physiology and discusses various prospects of its clinical utilization. Ever increasing evidence indicates that melatonin has an immuno-hematopoietic role. In animal studies, melatonin provided protection against gram-negative septic shock, prevented stress-induced immunodepression, and restored immune function after a hemorrhagic shock. In human studies, melatonin amplified the antitumoral activity of interleukin-2. Melatonin has been proven as a powerful cytostatic drug in vitro as well as in vivo. In the human clinical field, melatonin appears to be a promising agent either as a diagnostic or prognostic marker of neoplastic diseases or as a compound used either alone or in combination with the standard cancer treatment. Utilization of melatonin for treatment of rhythm disorders, such as those manifested in jet lag, shift work or blindness, is one of the oldest and the most successful clinical application of this chemical. Low doses of melatonin applied in controlled-release preparation were very effective in improving the sleep latency, increasing the sleep efficiency and rising sleep quality scores in elderly, melatonin-deficient insomniacs. In the cardiovascular system, melatonin seems to regulate the tone of cerebral arteries; melatonin receptors in vascular beds appear to participate in the regulation of body temperature. Heat loss may be the principal mechanism in the initiation of sleepiness caused by melatonin. The role of melatonin in the development of migraine headaches is at present uncertain but more research could result in new ways of treatment. Melatonin is the major messenger of light-dependent periodicity, implicated in the seasonal reproduction of animals and pubertal development in humans. Multiple receptor sites detected in brain and gonadal tissues of birds and mammals of both sexes indicate that melatonin exerts a direct effect on the vertebrate reproductive organs. In a clinical study, melatonin has been used successfully as an effective female contraceptive with little side effects. Melatonin is one of the most powerful scavengers of free radicals. Because it easily penetrates the blood-brain barrier, this antioxidant may, in the future, be used for the treatment of Alzheimer's and Parkinson's diseases, stroke, nitric oxide, neurotoxicity and hyperbaric oxygen exposure. In the digestive tract, melatonin reduced the incidence and severity of gastric ulcers and prevented severe symptoms of colitis, such as mucosal lesions and diarrhea

Gastrointestinal melatonin: localization, function, and clinical relevance.

Bubenik GA.

Dig Dis Sci. 2002 Oct; 47(10):2336-48.

The gastrointestinal tract of vertebrate species is a rich source of extrapineal melatonin. The concentration of melatonin in the gastrointestinal tissues surpasses blood levels by 10-100 times and there is at least 400x more melatonin in the gastrointestinal tract than in the pineal gland. The gastrointestinal tract contributes significantly to circulating concentrations of melatonin, especially during the daytime and melatonin may serve as an endocrine, paracrine, or autocrine hormone influencing the regeneration and function of epithelium, enhancing the immune system of the gut, and reducing the tone of gastrointestinal muscles. As binding sites for melatonin exhibit circadian variation in various species, it has been hypothesized that some melatonin found in the gastrointestinal tract might be of pineal origin. Unlike the photoperiodically regulated production of melatonin in the pineal, the release of gastrointestinal melatonin seems to be related to the periodicity of food intake. Phylogenetically, melatonin and its binding sites were detected in the gastrointestinal tract of lower vertebrates, birds, and mammals. Melatonin was found also in large quantities in the embryonic tissue of the mammalian and avian gastrointestinal tract. Food intake and, paradoxically, also longterm food deprivation resulted in an increase of tissue and plasma concentrations of melatonin. Melatonin release may have a direct effect on many gastrointestinal tissues but may also well influence the digestive tract indirectly, via the central nervous system and the sympathetic and parasympathetic nerves. Melatonin prevents ulcerations of gastrointestinal mucosa by an antioxidant action, reduction of secretion of hydrochloric acid, stimulation of the immune system, fostering epithelial regeneration, and increasing microcirculation. Because of its unique properties, melatonin could be considered for prevention or treatment of colorectal cancer, ulcerative colitis, gastric ulcers, irritable bowel syndrome, and childhood colic

Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review.

Caro JJ, Salas M, Ward A, et al.

Cancer. 2001 Jun 15; 91(12):2214-21.

BACKGROUND: Anemia is common in cancer patients, although the prevalence is influenced both by the type of malignancy and the choice of treatment. Individual studies have compared the survival of patients with and without anemia and have shown reduced survival times in patients with various malignancies, including carcinoma of the lung, cervix, head and neck, prostate, lymphoma, and multiple myeloma. The objective of this study was to systematically review, to summarize, and to obtain an overall estimate of the effect of anemia on survival in patients with malignant disease. METHODS: A comprehensive literature review was carried out using the MEDLINE data base and reviewing the reference lists from published studies. Two hundred papers were identified. Of these, 60 papers that reported the survival of cancer patients according to either hemoglobin levels or the presence of anemia were included. Among these papers, 25% related to patients with lung carcinoma, 17% related to patients with head and neck carcinoma, 12% related to patients with multiple myeloma, 10% related to patients with prostate carcinoma, 8% related to patients with cervicouterine carcinoma, 7% related to patients with leukemia, 5% related to patients with lymphoma, and 16% related to patients with other types of malignancies. RESULTS: The relative risk of death increased by 19% (95% confidence interval, 10-29%) in anemic patients with lung carcinoma, by 75% (37-123%) in anemic patients with head and neck carcinoma, by 47% (21-78%) in anemic patients with prostate carcinoma, and by 67% (30-113%) in anemic patients with lymphoma. The overall estimate increase in risk was 65% (54-77%). CONCLUSIONS: Anemia is associated with shorter survival times for patients with lung carcinoma, cervicouterine carcinoma, head and neck carcinoma, prostate carcinoma, lymphoma, and multiple myeloma

Two- and three-dimensional cell structures govern epidermal growth factor survival function in human bladder carcinoma cell lines.

Dangles V, Femenia F, Laine V, et al.

Cancer Res. 1997 Aug 15; 57(16):3360-4.

Human bladder carcinomas often express high levels of the epidermal growth factor (EGF) receptor. In three human bladder carcinoma cell lines (OBR, T24, and 647V), we show that two EGF receptor ligands, namely EGF and transforming growth factor alpha, enhanced the apoptosis due to serum starvation on cells cultured as monolayers. Conversely, EGF and transforming growth factor alpha prevented apoptosis when the same serum-starved cells were cultured as three-dimensional spheroids. Both stimulation and inhibition of apoptosis by EGF were associated with p21 WAF1/CIP1 overexpression. In 647V spheroids, EGF protection against radiation-induced apoptosis was negated by genistein and tyrphostin AG1478, suggesting that blockade of the EGF signal transduction in patients with bladder cancer may improve the radiotherapy efficacy

Therapeutic perspectives for melatonin agonists and antagonists.

Delagrange P, Atkinson J, Boutin JA, et al.

J Neuroendocrinol. 2003 Apr; 15(4):442-8.

Melatonin is a neurohormone synthesized in the pineal gland during the dark period in all species, including humans. The diversity and differences in melatonin receptor distribution in the brain and extracerebral organs suggest multiple functional roles for melatonin. Administration of melatonin agonists reduces neophobia and treatment with a melatonin antagonist during the dark period reverses the anxiolytic-like effect of endogenous melatonin. Chronic treatment with agonists prevents various perturbations induced by chronic mild stress. Melatonin in vivo directly constricts cerebral arterioles in rats and decreases the lower limit of cerebral blood flow autoregulation, suggesting that melatonin may diminish the risk of hypoperfusion-induced cerebral ischemia. At the extracerebral level, melatonin regulates intestinal motility in rats. The intestinal postprandial motor response is shorter in the dark phase than in the light phase and this reduction is reversed in animals pretreated with a melatonin antagonist. Moreover, melatonin reduces the duration of cholecystokinin excitomotor effect. Endogenous melatonin may modulate intestinal motility to coordinate intestinal functions such as digestion and transit and control the metabolism of the animal. An adipocyte melatonin binding site may also participate in this control. Melatonin is involved in a wide range of physiological functions. The question remains as to whether evolution, adaptation and diurnal life have modified the physiological role of melatonin in humans. Moreover, the functional role of each of the receptor subtypes has to be characterized to design selective ligands to treat specific diseases

Striking regression of radiation-induced fibrosis by a combination of pentoxifylline and tocopherol.

Delanian S.

Br J Radiol. 1998 Aug; 71(848):892-4.

Radiation-induced fibrosis (RIF) is a terminal sequela to irradiation that does not regress spontaneously. A preliminary study of a combination of pentoxifylline (PTX) and tocopherol (vit-E) has shown clinical activity with 50% superficial RIF regression at 6 months in half of the patients studied. The present report is of a 67-year-old woman presenting with bulky cervicothoracic RIF who, 10 years previously, had received radiochemotherapy for a small cell thyroid carcinoma to a dose of 50 Gy, with severe acute side-effects. She had palpable cervicosternal fibrosis measuring 10 x 8 cm, with local inflammatory signs and functional consequences (cough, restricted cervical movement, dyspnoea and bronchitis) with a SOMA scale for grading the long-term side effects of radiation therapy of 19/14. CT showed deep RIF extending from the vocal cords to the carina, with laryngotracheal compression but without cancer recurrence. PTX (800 mg d-1) and vit-E (1000 U d-1), orally administered daily for 18 months, were well tolerated. The patient exhibited clinical regression and functional improvement. The linear dimensions and SOMA scale were, respectively, 8 x 6 cm and 11 at 6 months; 4 x 4 cm and 7 at 12 months; and complete response with no measurable RIF and 1 at 18 months. This is the first time that the combination of PTX and vit-E has had a significant antifibrotic effect by completely reversing deep RIF as shown by CT scan normalization

Taurine deficiency after intensive chemotherapy and/or radiation.

Desai TK, Maliakkal J, Kinzie JL, et al.

Am J Clin Nutr. 1992 Mar; 55(3):708-11.

Taurine, a nonessential amino acid (AA), is the most abundant free AA in the intracellular space. We measured plasma AA concentrations in 36 patients 7-28 d after intensive chemotherapy and/or radiation. Plasma taurine concentrations were uniformly low in all patients (20.0 +/- 6.4 mumol/L, mean +/- SD). Plasma taurine in 11 healthy volunteer control subjects was 45.0 +/- 20.3 mumol/L (P less than 0.001). Other AA concentrations, specifically those of precursor AAs methionine and cystine, were normal. We prospectively measured plasma AA concentrations in 12 patients before starting and 6-10 d after completing intensive cytotoxic treatment. Values before treatment were 37.2 +/- 11.6, 109.6 +/- 30.7, and 18.5 +/- 4.8 for taurine, cystine, and methionine, respectively, and were 24.3 +/- 6.0, 111.2 +/- 23.8, and 24.0 +/- 14.5 after treatment. Pretreatment plasma taurine correlated directly with the magnitude of decrease in plasma taurine during cytotoxic treatment (n = 12, r = 0.85, P less than 0.01). Intensive cytotoxic chemotherapy and/or radiation leads to a reduction in plasma taurine concentrations without any change in its precursor AAs, methionine and cystine. The clinical relevance of plasma taurine depletion will need further study

Characterization of the biological activity of gamma-glutamyl-Se-methylselenocysteine: a novel, naturally occurring anticancer agent from garlic.

Dong Y, Lisk D, Block E, et al.

Cancer Res. 2001 Apr 1; 61(7):2923-8.

Gamma-glutamyl-Se-methylselenocysteine (GGMSC) has recently been identified as the major Se compound in natural garlic and selenized garlic. Our working hypothesis is that GGMSC serves primarily as a carrier of Se-methylselenocysteine (MSC), which has been demonstrated in past research to be a potent cancer chemopreventive agent in animal carcinogenesis bioassays. The present study was designed to examine the in vivo responses to GGMSC or MSC using a variety of biochemical and biological end points, including (a) urinary Se excretion as a function of bolus dose; (b) tissue Se accumulation profile; (c) anticancer efficacy; and (d) gene expression changes as determined by cDNA array analysis. Our results showed that like MSC, GGMSC was well absorbed p.o., with urinary excretion as the major route for eliminating excess Se. When fed chronically, the profile of Se accumulation in various tissues was very comparable after treatment with either GGMSC or MSC. In rats that had been challenged with a carcinogen, supplementation with either GGMSC or MSC resulted in a lower prevalence of premalignant lesions in the mammary gland, and fewer mammary carcinomas when these early lesions were allowed to progress. More importantly, we found that a short term GGMSC/MSC treatment schedule of 4 weeks immediately after carcinogen dosing was sufficient to provide significant cancer protection, even in the absence of a sustained exposure past the initial 4-week period. With the use of the Clontech Atlas Rat cDNA Array, we further discovered that the gene expression changes induced in mammary epithelial cells of rats that were given either GGMSC or MSC showed a high degree of concordance. On the basis of the collective biology, biochemistry, and molecular biology data, we conclude that GGMSC is an effective anticancer agent with a mechanism of action very similar to that of MSC

Therapeutic potential of curcumin in human prostate cancer. II. Curcumin inhibits tyrosine kinase activity of epidermal growth factor receptor and depletes the protein.

Dorai T, Gehani N, Katz A.

Mol Urol. 2000; 4(1):1-6.

PURPOSE: In a search for alternative and preventive therapies for prostate cancer, attention was focused on the ways in which curcumin (Turmeric), used in food and medicine in India for centuries, could interfere with the growth factor signaling pathways in both androgen-dependent and androgen-independent prostate cancer cells, as exemplified by the epidermal growth factor receptor (EGF-R) signaling. MATERIALS AND METHODS: The androgen-sensitive LNCaP and androgen-insensitive PC-3 cell lines were grown in 5 to 50 microM curcumin and analyzed for EGF-R protein by Western blotting and for EGF-R tyrosine kinase activity. RESULTS: Curcumin was a potent inhibitor of EGF-R signaling, and it accomplished this effect by three different means (1) down regulating the EGF-R protein; (2) inhibiting the intrinsic EGF-R tyrosine kinase activity; and (3) inhibiting the ligand-induced activation of the EGF-R. CONCLUSIONS: These results, taken together with our previous results that curcumin can induce apoptosis in both androgen-dependent and androgen-independent prostate cancer cells, support our view that curcumin may be a novel modality by which one can interfere with the signal transduction pathways of the prostate cancer cell and prevent it from progressing to its hormone-refractory state

Green tea and thermogenesis: interactions between catechin-polyphenols, caffeine and sympathetic activity.

Dulloo AG, Seydoux J, Girardier L, et al.

Int J Obes Relat Metab Disord. 2000 Feb; 24(2):252-8.

The thermogenic effect of tea is generally attributed to its caffeine content. We report here that a green tea extract stimulates brown adipose tissue thermogenesis to an extent which is much greater than can be attributed to its caffeine content per se, and that its thermogenic properties could reside primarily in an interaction between its high content in catechin-polyphenols and caffeine with sympathetically released noradrenaline (NA). Since catechin-polyphenols are known to be capable of inhibiting catechol-O-methyl-transferase (the enzyme that degrades NA), and caffeine to inhibit trancellular phosphodiesterases (enzymes that break down NA-induced cAMP), it is proposed that the green tea extract, via its catechin-polyphenols and caffeine, is effective in stimulating thermogenesis by relieving inhibition at different control points along the NA-cAMP axis. Such a synergistic interaction between catechin-polyphenols and caffeine to augment and prolong sympathetic stimulation of thermogenesis could be of value in assisting the management of obesity. International Journal of Obesity (2000) 24, 252-258

A 2-week pretreatment with 13-cis-retinoic acid + interferon-alpha-2a prior to definitive radiation improves tumor tissue oxygenation in cervical cancers.

Dunst J, Hansgen G, Krause U, et al.

Strahlenther Onkol. 1998 Nov; 174(11):571-4.

BACKGROUND: We have evaluated the tumor tissue pO2 in cervical cancers in patients treated with 13-cis-retinoic acid and interferon-alpha-2a prior to and during radiotherapy. PATIENTS AND METHODS: From June 1995 through April 1997, 22 patients with squamous cell carcinoma FIGO IIB/III of the cervix who were scheduled for definitive radiotherapy with curative intent received additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) plus interferon-alpha-2a (IFN-alpha-2a) as part of a phase-II protocol. cRA/IFN-alpha-2a started 14 days prior to radiotherapy (1 mg per kilogramme body weight cRA orally daily plus 6 x 10(6) IU IFN-alpha-2a subcutaneously daily). After this induction period, standard radiotherapy was administered (external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus HDR-brachytherapy). During radiotherapy, cRA/IFN-alpha-2a treatment was continued with 50% of the daily doses. Tumor tissue pO2-measurements were performed prior to and after the cRA/IFN-induction period as well as at 20 Gy and at the end of radiotherapy with an Eppendorf-pO2-histograph. RESULTS: In 11 out of the 22 patients, pO2-measurements were performed prior to the cRA/IFN-induction therapy. The median pO2 of these untreated tumors was 17.7 +/- 16.3 mm Hg. The relative frequency of hypoxic readings with pO2-values below 5 mm Hg ranged from 0% to 60.6% (mean 24.3 +/- 21.0%). After the 2-week induction period with cRA/IFN, the median pO2 had increased from 17.7 +/- 16.3 mm Hg to 27.6 +/- 19.1 mm Hg (not significant). In all 5 patients with hypoxic tumors prior to cRA/IFN (median pO2 of 10 mm Hg or less), the median pO2 was above 20 mm Hg after the 2-week cRA/IFN-induction. In this subgroup of hypoxic tumors, the median pO2 increased from 6.3 +/- 2.7 mm Hg to 27.0 +/- 5.6 mm Hg (p = 0.004, t-test for paired samples). The frequency of hypoxic readings (pO2-values < 5 mm Hg) decreased from 44.7 +/- 17.1% to 2.0 +/- 2.5% (p = "0.012," t-test for paired samples). There was, however, no obvious volume reduction after 14 weeks of cRA/IFN on clinical examination. A complete clinical remission of the local tumor was observed in 19/22 patients after radiotherapy and additional cRA/IFN-alpha-2a-treatment. In primarily hypoxic tumors (with a median pO2 below 10 mm Hg prior to treatment), 4/5 achieved complete remission. CONCLUSIONS: Pretreatment with cRA/IFN improves oxygenation of primarily hypoxic cervical cancers. The mechanisms of action remain unclear and further investigation of the combination regimen is recommended

Oxygenation of cervical cancers during radiotherapy and radiotherapy + cis-retinoic acid/interferon.

Dunst J, Hansgen G, Lautenschlager C, et al.

Int J Radiat Oncol Biol Phys. 1999 Jan 15; 43(2):367-73.

PURPOSE: We have evaluated the tumor tissue pO2 in cervical cancers during radiotherapy with special emphasis on the course of the pO2 in primarily hypoxic tumors and in patients treated with radiotherapy plus 13-cis-retinoic acid/interferon-alpha-2a. METHODS AND MATERIALS: From June 1995 through April 1997, 49 patients with squamous cell carcinoma FIGO IIB-IVA of the cervix who were treated with definitive radiotherapy with curative intent underwent polarographic measurement of tumor tissue pO2 with an Eppendorf pO2-histograph prior to and during radiation treatment. Radiotherapy consisted of external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus high dose rate (HDR) brachytherapy. Twenty-two patients had additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) and interferon-alpha-2a (IFN-alpha-2a). Therapy with cRA/IFN in these patients started 2 weeks before radiotherapy; during this induction period, cRA was administered in a dosage of 1 mg per kilogram body weight orally daily and IFN-alpha-2a in a dosage of 6x10(6) I.U. subcutaneously daily. After start of external radiotherapy (XRT), cRA/IFN was continued concomitantly with radiotherapy in reduced doses (0.5 mg cRA per kg body weight orally daily plus 3x10(6) I.U. IFN-alpha-2a subcutaneously three times weekly until the end of the radiation treatment). PO2 measurements were performed prior to radiotherapy, at 20 Gy, and at the end of radiotherapy. RESULTS: A poor oxygenation defined as a median pO2 of 10 mm Hg or less was present in 15/38 tumors (39%) in which measurements prior to any treatment were done. Low pO2 readings below 5 mm Hg were present in 70% of all tumors prior to treatment. In 13 of 15 hypoxic tumors, pO2 measurements at 19.8 Gy were performed. In these tumors, a significant increase of the median pO2 from 6.0+/-3.1 mm Hg to 20.7+/-21.2 mm Hg was found, p10 mm Hg), 20/23 (87%) achieved a clinically complete response. In patients with primarily hypoxic tumors, 6/6 patients whose primarily hypoxic tumors showed an increase of the median pO2 above 10 mm Hg at 19.8 Gy achieved a complete remission (CR). In contrast, only 4/7 patients with a low pretreatment and persisting low median pO2 achieved a CR. CONCLUSIONS: There are evident changes in the oxygenation of cervical cancers during a course of fractionated radiotherapy. In primarily hypoxic tumors, a significant increase of the median pO2 was found. An additional treatment with cis-retinoic acid/interferon further improved the oxygenation. An impact of the different patterns of oxygenation on local control is to be evaluated

Clinical trial of atmospheric oxygen breathing during radiotherapy for cancer of the oropharynx.

Evans JC, Cavanaugh PJ.

Radiol Clin (Basel). 1975; 44(3):210-3.

A randomized clinical trial of atmospheric oxygen breathing during radiotherapy of advanced cancer of the tonsillar region has been conducted. In order to achieve a high level of inspired oxygen, a closed system with a "head tent" was used. Over 2 years after treatment, 30 percent of the oxygen patients survived without evidence of disease compared to 17 percent in the control group

Strategies for reversing drug resistance.

Fojo T, Bates S.

Oncogene. 2003 Oct 20; 22(47):7512-23.

Drug resistance, intrinsic or acquired, is a problem for all chemotherapeutic agents. In this review, we examine numerous strategies that have been tested or proposed to reverse drug resistance. Included among these strategies are approaches targeting the apoptosis pathway. Although the process of apoptosis is complex, it provides several potential sites for therapeutic intervention. A variety of targets and approaches are being pursued, including the suppression of proteins inhibiting apoptosis using antisense oligonucleotides (ASOs), and small molecules targeted at proteins that modulate apoptosis. An alternate strategy is based on numerous studies that have documented methylation of critical regions in the genome in human cancers. Consequently, efforts have been directed at re-expressing genes, including genes that affect drug sensitivity, using 5-azacytidine and 2'-deoxy-5-azacytidine (DAC, decitabine) as demethylating agents. While this strategy may be effective as a single modality, success will most likely be achieved if it is used to modulate gene expression in combination with other modalities such as chemotherapy. At a more basic level, attempts have been made to modulate glutathione (GSH) levels. Owing to its reactivity and high intracellular concentrations, GSH has been implicated in resistance to several chemotherapeutic agents. Several approaches designed to deplete intracellular GSH levels have been pursued including the use of buthionine-(S,R)-sulfoxime (BSO), a potent and specific inhibitor of gamma-glutamyl cysteine synthetase (gamma-GCS), the rate-limiting step in the synthesis of GSH, a hammerhead ribozyme against gamma-GCS mRNA to downregulate specifically its levels and targeting cJun expression to reduce GSH levels. Alternate strategies have targeted p53. The frequent occurrence of p53 mutations in human cancer has led to the development of numerous approaches to restore wild-type (wt) p53. The goals of these interventions are to either revert the malignant phenotype or enhance drug sensitivity. The approach most extensively investigated has utilized one of several viral vectors. An alternate approach, the use of small molecules to restore wt function to mutant p53, remains an option. Finally, the conceptually simplest mechanism of resistance is one that reduces intracellular drug accumulation. Such reduction can be effected by a variety of drug efflux pumps, of which the most widely studied is P-glycoprotein (Pgp). The first strategy utilized to inhibit Pgp function relied on the identification of non-chemotherapeutic agents as competitors. Other approaches have included the use of hammerhead ribozymes against the MDR-1 gene and MDR-1-targeted ASOs. Although modulation of drug resistance has not yet been proven to be an effective clinical tool, we have learned an enormous amount about drug resistance. Should we succeed, these pioneering basic and clinical studies will have paved the road for future developments

The cure of advanced cancer by diet therapy: a summary of 30 years of clinical experimentation.

Gerson M.

Physiol Chem Phys. 1978; 10(5):449-64.

Thirty years of clinical experimentation has led to a successful therapy for advanced cancer. This therapy is based on the concepts (1) that cancer patients have low immuno-reactivity and generalized tissue damage, especially of the liver, and (2) that when the cancer is destroyed, toxic degradation products appear in the bloodstream which lead to coma and death from liver failure. The therapy consists of high potassium, low sodium diet, with no fats or oils, and minimal animal proteins. Juices of raw fruits and vegetables and of raw liver provide active oxidizing enzymes which facilitate rehabilitation of the liver. Iodine and niacin supplementation is used. Caffeine enemas cause dilation of bile ducts, which facilitates excretion of toxic cancer breakdown products by the liver and dialysis of toxic products from blood across the colonic wall. The therapy must be used as an integrated whole. Parts of the therapy used in isolation will not be successful. This therapy has cured many cases of advanced cancer

[The treatment of cutaneous radiation-induced fibrosis with pentoxifylline and vitamin E. An empirical report].

Gottlober P, Krahn G, Korting HC, et al.

Strahlenther Onkol. 1996 Jan; 172(1):34-8.

BACKGROUND: Radiation fibrosis represents a severe complication of radiation therapy; standardized treatment protocols are lacking so far. Surgical excision rarely results in complete healing. PATIENT AND METHODS: We report on a 58-year-old female patient who developed a squamous cell carcinoma within the fibrotic area of the irradiation field on the right chest, resulting from a radiotherapy following mastectomy for breast cancer 17 years ago. After surgical excision of the carcinoma a combined treatment with pentoxifylline tablets (3 x 400 mg/d p.o.) and vitamin-E capsules (1 x 400 mg/d p.o.) was initiated. Skin thickness was quantified by 20 MHz-ultrasound before and during treatment. RESULTS: The patient noted an increasing improvement of the condition of the affected skin starting from 4 months. A continuing decrease of skin thickness as documented by 20 MHz-ultrasound could be demonstrated from the 6th month on. The treatment was tolerated well, no side effects were observed. CONCLUSION: The data indicate a beneficial therapeutic effect of pentoxifylline and vitamin E on radiation-induced fibrosis. Little is known about the mechanism of action of this combined treatment protocol including pentoxifylline and vitamin E. Controlled clinical trials should be performed to confirm this observation

Prevalence of anemia in cancer patients undergoing radiotherapy: prognostic significance and treatment.

Harrison LB, Shasha D, Homel P.

Oncology. 2002; 63 Suppl 2:11-8.

As the antitumor activity of radiation is mediated via its interaction with oxygen to form labile free radicals, the intratumoral oxygen level has an important influence on the ability of radiation therapy to kill malignant cells. By decreasing the oxygen-carrying capacity of the blood, anemia may result in tumor hypoxia and may have a negative influence on the outcome of radiotherapy for various malignancies, even for small tumors not normally assumed to be hypoxic. In addition, anemia also has a negative effect on the quality of life of cancer patients, as evidenced by worsening fatigue. As a high proportion (about 50%) of cancer patients undergoing radiotherapy are anemic prior to or during treatment, strategies to correct anemia and/or the resultant tumor hypoxia are increasingly being considered an important component of treatment. In particular, epoetin alfa (recombinant human erythropoietin), which has proved an effective and well-tolerated means of raising hemoglobin levels in anemic patients receiving radiotherapy, potentially could reverse the negative prognostic influence of a low hemoglobin in patients with certain malignancies. Radiation oncologists need to be aware of the possibility of anemia in cancer patients undergoing radiotherapy so that timely intervention can be instituted whenever anemia is diagnosed

Caffeine enhanced radiosensitivity of rat tumor cells with a mutant-type p53 by inducing apoptosis in a p53-independent manner.

Higuchi K, Mitsuhashi N, Saitoh J, et al.

Cancer Lett. 2000 May 1; 152(2):157-62.

The radiosensitizing effects of caffeine on two rat yolk sac tumor cell lines with a different p53 status were investigated. A reduction of radiation-induced G(2) arrest was caused by caffeine at a concentration of 2 mM in both cell lines. The reduction of survival was observed in a combination of radiation and 2 mM caffeine only in a lower radiation dose range, but not in a higher dose range in NMT-1 with a wild type p53. Radiosensitization of caffeine was recognized even in a higher dose range for cells with a mutant-type p53. Apoptosis, which was not prominent after irradiation alone or caffeine treatment alone, was induced by irradiation in combination with caffeine in cells with a mutant-type p53 through a p53-independent pathway

Microregional blood flow in murine and human tumours assessed using laser Doppler microprobes.

Hill SA, Pigott KH, Saunders MI, et al.

Br J Cancer Suppl. 1996 Jul; 27:S260-S263.

A multichannel laser Doppler system has been used to measure microregional fluctuations in perfusion in the HT29 human tumour xenograft and in patients with advanced malignant disease. A comparison is made with previously obtained data for the SaF, a transplantable murine tumour. The 300 microns diameter probes recorded fluctuations in erythrocyte flux in tumour microregions with an estimated volume of 10(-2) mm3. Of the 66 human tumour microregions sampled, 26% showed a change in erythrocyte flux by a factor of 2 or more over the 60 min measurement period, compared with 37% of HT29 and 48% of SaF microregions. In each of the studies more than 50% of changes were completed within 20 min, although slower changes were more common in the human tumours than in the experimental systems. Within the 1 h monitoring period at least 30% of the changes were reversed (human tumours 30%, HT29 45%, SaF 31%). These findings demonstrate that microregional changes in erythrocyte flux, consistent with transient, perfusion-driven changes in oxygenation, are a feature of human malignancies as well as experimental transplanted tumours

Genistein potentiates the radiation effect on prostate carcinoma cells.

Hillman GG, Forman JD, Kucuk O, et al.

Clin Cancer Res. 2001 Feb; 7(2):382-90.

We have shown previously that genistein, the major isoflavone in soybean, inhibited the growth of human prostate cancer cells in vitro by affecting the cell cycle and inducing apoptosis. To augment the effect of radiation for prostate carcinoma, we have now tested the combination of genistein with photon and neutron radiation on prostate carcinoma cells in vitro. The effects of photon or neutron radiation alone or genistein alone or both combined were evaluated on DNA synthesis, cell growth, and cell ability to form colonies. We found that neutrons were more effective than photons for the killing of prostate carcinoma cells in vitro, resulting in a relative biological effectiveness of 2.6 when compared with photons. Genistein at 15 microM caused a significant inhibition in DNA synthesis, cell growth, and colony formation in the range of 40-60% and potentiated the effect of low doses of 200-300 cGy photon or 100-150 cGy neutron radiation. The effect of the combined treatment was more pronounced than with genistein or radiation alone. Our data indicate that genistein combined with radiation inhibits DNA synthesis, resulting in inhibition of cell division and growth. Genistein can augment the effect of neutrons at doses approximately 2-fold lower than photon doses required to observe the same efficacy. These studies suggest a potential of combining genistein with radiation for the treatment of localized prostate carcinoma

Hypoxia and Radiation Response in Human Tumors.

Hockel M, Schlenger K, Mitze M, et al.

Semin Radiat Oncol. 1996 Jan; 6(1):3-9.

This study demonstrates by an updated analysis of an ongoing prospective study that tumor oxygenation, as measured with a validated standardized polarographic needle electrode method before treatment, powerfully predicts the prognosis of patients receiving radiotherapy for intermediate and advanced stage cancer of the uterine cervix. First evidence for a host component in tumor oxygenation based on a significant correlation between median pO(2) values determined in normal subcutaneous fatty tissue and in cervical cancer is also presented. Further investigations are necessary to clarify whether tumor hypoxia is just a marker of intrinsic tumor aggressiveness or whether the negative impact of tumor hypoxia on survival is related to radiobiological mechanisms caused by hypoxia per se, which may include (1) the reduced oxygen enhancement effect, (2) increased radioresistance due to expression of genes for cell cycle delay and stress proteins, and/or (3) accelerated tumor progression to more radioresistant and metastatic variants by increased genetic heterogeneity

[Favorable effect of sildenafil on erectile dysfunction in patients after radiotherapy for prostate cancer; randomised, double-blind, placebo-controlled crossover study].

Incrocci L, Hop WC, Slob AK.

Ned Tijdschr Geneeskd. 2003 Aug 30; 147(35):1687-90.

OBJECTIVE: To determine the efficacy of sildenafil in patients with erectile dysfunction after external beam radiotherapy for prostate cancer. DESIGN: Randomised, double-blind, placebo-controlled, crossover study. METHOD: A total of 406 patients with erectile dysfunction reported in their medical records who had completed external beam radiotherapy at least 6 months prior to the study, were approached by letter. Sixty patients were included in a study which lasted 12 weeks. They received 50 mg of sildenafil citrate or placebo for two weeks; during week 2 the dose could be increased to 100 mg in the case of unsatisfactory erectile response. At week 6 patients crossed over to the alternative treatment. Data were collected using the validated 'International index of erectile function' (IIEF) questionnaire, and side-effects were recorded. Patients were given the possibility of continuing to a 6-week open-label phase. RESULTS: The mean age of those participating was 68 years. All patients completed the double-blind phase. For the majority f questions in the IIEF questionnaire, there was a significant increase in mean scores from baseline with sildenafil, but of the patients with sildenafil, versus 18% with placebo. Ninety percent of the patients required a dose adjustment to 100 mg sildenafil, and 100% of the patients in the placebo group increased the dose. Side-effects were mild or moderate. Patients who proceeded to the open-label phase reported the same results as in the double-blind phase. CONCLUSION: Sildenafil improved erectile function in about half of the patients with erectile dysfunction after external beam radiotherapy for prostate cancer, and it was well tolerated

Comparison of selenium and sulfur analogs in cancer prevention.

Ip C, Ganther HE.

Carcinogenesis. 1992 Jul; 13(7):1167-70.

Several organoselenium compounds have been shown to have powerful anticarcinogenic activity. In view of certain similarities between selenium and sulfur biochemistry, we have evaluated the chemopreventive efficacy of three pairs of analogs using the 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor model in rats. The compounds tested were selenocystamine/cysteamine, Semethylselenocysteine/S-methylcysteine, selenobetaine/sulfobetaine. In the first study, each agent was added to the basal AIN-76A diet and was given before and continued after DMBA treatment until the end. All three selenium compounds were active; a 50% inhibition was achieved at approximately 25 x 10(-6) mol/kg with Se-methylselenocysteine and selenobetaine and at approximately 40 x 10(-6) mol/kg with selenocystamine. In the sulfur series, only cysteamine and S-methylcysteine produced anticancer activity, and the levels required for comparable responses were 500- to 750-fold higher compared to the corresponding selenium analogs. Sulfobetaine was inactive even when present at near maximally tolerated levels. In the second study, Se-methylselenocysteine and S-methylcysteine were chosen for further examination during the initiation and post-initiation phases of mammary carcinogenesis. Se-Methylselenocysteine was effective when it was given either before or after DMBA administration. In contrast, S-methylcysteine was effective only after DMBA treatment. Thus, compared to the sulfur structural analogs, selenium compounds are much more active in cancer protection and may have a multi-modal mechanism in preventing cellular transformation as well as in delaying or inhibiting the expression of malignancy after carcinogen exposure

Chemoprevention of mammary cancer with Se-allylselenocysteine and other selenoamino acids in the rat.

Ip C, Zhu Z, Thompson HJ, et al.

Anticancer Res. 1999 Jul; 19(4B):2875-80.

The present study examined the mammary cancer chemopreventive activity of Se-methylselenocysteine, Se-propylselenocysteine and Se-allylselenocysteine in the rat methylnitrosourea (MNU) model. Each compound was supplemented in the diet at a level of 2 ppm Se for the entire duration of the experiment after MNU dosing. Se-Allylselenocysteine was the most active and caused a reduction in total tumor yield by 86%. Se-Methylselenocyteine and Se-propylselenocysteine were similar but less effective, and both produced a decrease of about 50% in tumorigenesis. All three compounds were very well absorbed through the gastrointestinal tract. However, more selenium was excreted in urine after gavaging with Se-propylselenocysteine or Se-allylselenocysteine compared with Se-methylselenocysteine. Analysis of selenium in the mammary gland and other organs showed that tissue selenium levels did not appear to be correlated with differences in chemopreventive activity. A lyase activity capable of catalyzing scission of the Se-alkyl group from the remainder of the amino acid was demonstrated. This activity was found to be high in liver and kidney, but relatively low in mammary gland and intestine. Minimal variations in enzyme activity towards each of the substrates were observed. Our results support the concept that Se-alkylselenoamino acids could be used as precursors for delivering the Se-alkyl moiety and that intrinsic chemical differences in the Se-alkyl substituent of the test compounds are likely to be important determinants of their biological effects

Methylselenocysteine modulates proliferation and apoptosis biomarkers in premalignant lesions of the rat mammary gland.

Ip C, Dong Y.

Anticancer Res. 2001 Mar; 21(2A):863-7.

In the rat mammary carcinogenesis model, premalignant lesions known as intraductal proliferations (IDPs) are detectable within a few weeks after carcinogen treatment. These early transformed colonies are the precursors for the eventual formation of carcinomas. Our past research indicated that methylselenocysteine added to the diet of rats reduced the development of IDPs of all sizes (the size of each IDP was estimated operationally by the number of 5-micron serial sections showing the same pathology). The appearance of an IDP lesion represents a balance between cell proliferation and cell death. The modulation of these two cellular events by methylselenocysteine was investigated. The abdominal-inguinal mammary gland was excised 6 weeks after MNU administration. Proliferation and apoptosis were evaluated by BrdU labeling and the TUNEL assay, respectively. The expression levels of several cell cycle and apoptosis regulatory proteins, including cyclin D1, cyclin A, p27, p16, bcl-2, box and bak, were also assessed. All of the above endpoints were quantified by immunohistochemistry in paraffin-embedded sections. The results showed that the magnitude of the response to methylselenocysteine intervention seemed to depend on the size of the IDP lesion. For the purpose of this study, the small and large lesions were classified as those containing 30 serial sections, respectively. With the small lesions, methylselenocysteine significantly inhibited BrdU labeling and the expression of cyclin D1 and cyclin A, but increased the expression of p27. Interesting, only p27 was upregulated in the larger IDP lesions, while BrdU labeling and the cyclins were not affected. It is possible that the transformed phenotype becomes less sensitive to selenium-mediated arrest of proliferation once it progresses to a more advanced pathological stage. In contrast, methylselenocysteine stimulated apoptosis (TUNEL assay) by 3 to 4 fold, and this increase was evident in both the small and large IDP lesions. Consistent with the induction of apoptosis, a reduced expression of bcl-2 was also observed in the methylselenocysteine group. In summary, our data suggest that exposure to methylselenocysteine blocks clonal expansion of premalignant lesions at an early stage. This is achieved by simultaneously modulating certain molecular pathways that are responsible for inhibiting cell proliferation and enhancing apoptosis

Indicators of free radical activity in patients developing radiation pneumonitis.

Jack CI, Cottier B, Jackson MJ, et al.

Int J Radiat Oncol Biol Phys. 1996 Jan 1; 34(1):149-54.

PURPOSE: Radiation pneumonitis is thought to occur as the result of excess free radical generation following radiotherapy. Various in vitro studies have shown that large doses of irradiation can cause membrane lipid peroxidation and the oxidation of protein sulphuryl groups. We, therefore, studied two circulating markers of lipid peroxidation and an indicator of "catalytic iron" (potentially available iron to catalyze the generation of free radicals) in patients undergoing radiotherapy. METHODS AND MATERIALS: The 9,11 diene conjugate of 9,12 linoleic acid, expressed as their molar ratio (percentage molar ratio (MR)) and thiobarbituric acid reactive acid-substances (TBARS), as well as levels of circulating desferrioxamine-chelatable iron assay, were assayed. Serial blood samples were taken over a 3-month period in 25 patients with inoperable nonsmall cell lung cancer. RESULTS: Ten patients developed radiation pneumonitis. The patients who developed pneumonitis showed a tendency for the serum percentage molar ratio to increase after a week. The change in the percentage molar ratio between Time 0 and 1 week of radiotherapy was significantly higher in the group that subsequently developed pneumonitis compared to the group that did not (p = 0.002). The initial serum TBARS levels in patients were not significantly elevated compared to controls and there was no difference in the serum TBARS levels in the pneumonitis and nonpneumonitis groups throughout the study period. After 1 week of radiotherapy the group that subsequently developed pneumonitis had a significantly higher level of desferrioxamine-chelatable iron (DFx-iron) compared with the nonpneumonitis group (p = 0.05). CONCLUSION: These data suggest that both the percentage MR and DFx-iron appear to reflect an increased susceptibility to develop radiation pneumonitis and after 1 week of radiotherapy they indicate patients who are likely to subsequently develop pneumonitis. Hence, these indicators could indicate the group of patients that could benefit from intervention therapies with antioxidants

Esophageal cancer and the esophagus: challenges and potential strategies for selective cytoprotection of the tumor-bearing organ during cancer treatment.

Jatoi A, Thomas CR, Jr.

Semin Radiat Oncol. 2002 Jan; 12(1 Suppl 1):62-7.

Esophageal cancer is treated optimally with a combined-modality approach according to most clinical investigators. Cytotoxic chemotherapy and ionizing radiotherapy, given in a concomitant schedule, has yielded superior survival rates compared with radiotherapy alone. However, mucosal toxicity from such treatment may compromise quality of life and may mandate an unscheduled break in therapy in some patients who do not respond readily to standard treatments such as antacids; combinations of viscous xylocaine, aluminum hydroxide-magnesium carbonate, and diphenhydramine hydrochloride; oral liquid morphine sulfate, hydrocodone bitartrate, or acetaminophen. Hence, a number of alternative strategies that are designed to either prevent or limit toxicity to normal tissues without diminishing the antitumor effect are being tested. These include the use of conformal radiotherapy treatment planning techniques, amifostine (Ethyol, WR-2721), gene therapy via intratumoral injection of manganese superoxide dismutase-plasmid/liposome, glutamine, melatonin, omega-3-polyunsaturated fatty acids, transforming growth factor, flavonoid compounds, probucol, and keratinizing growth factor. An ongoing phase 2 trial by the North Central Cancer Treatment Group (NCCTG) may help clarify a role for cytoprotectants in patients receiving combined-modality therapy for esophageal cancer

Selenium-induced inhibition of angiogenesis in mammary cancer at chemopreventive levels of intake.

Jiang C, Jiang W, Ip C, et al.

Mol Carcinog. 1999 Dec; 26(4):213-25.

The trace element nutrient selenium (Se) has been shown to possess cancer-preventive activity in both animal models and humans, but the mechanisms by which this occurs remain to be elucidated. Because angiogenesis is obligatory for the genesis and growth of solid cancers, we investigated, in the study presented here, the hypothesis that Se may exert its cancer-preventive activity, at least in part, by inhibiting cancer-associated angiogenesis. The effects of chemopreventive levels of Se on the intra-tumoral microvessel density and the expression of vascular endothelial growth factor in 1-methyl-1-nitrosourea-induced rat mammary carcinomas and on the proliferation and survival and matrix metalloproteinase activity of human umbilical vein endothelial cells in vitro were examined. Increased Se intake as Se-enriched garlic, sodium selenite, or Se-methylselenocysteine led to a significant reduction of intra-tumoral microvessel density in mammary carcinomas, irrespective of the manner by which Se was provided: continuous exposure (7-wk feeding) with a chemoprevention protocol or acute bolus exposure (3 d) after carcinomas had established. Compared with the untreated controls, significantly lower levels of vascular endothelial growth factor expression were observed in a sizeable proportion of the Se-treated carcinomas. In contrast to the mammary carcinomas, the microvessel density of the uninvolved mammary glands was not altered by Se treatment. In cell culture, direct exposure of human umbilical vein endothelial cells to Se induced cell death predominantly through apoptosis, decreased the gelatinolytic activities of matrix metalloproteinase-2, or both. These results indicate a potential for Se metabolites to inhibit key attributes (proliferation, survival, and matrix degradation) of endothelial cells critical for angiogenic sprouting. Therefore, inhibition of angiogenesis associated with cancer may be a novel mechanism for the anticancer activity of Se in vivo, and multiple mechanisms are probably involved in mediating the anti-angiogenic activity

Structure-activity relationships for G2 checkpoint inhibition by caffeine analogs.

Jiang X, Lim LY, Daly JW, et al.

Int J Oncol. 2000 May; 16(5):971-8.

Caffeine inhibits the G2 checkpoint activated by DNA damage and enhances the toxicity of DNA-damaging agents towards p53-defective cancer cells. The relationship between structure and G2 checkpoint inhibition was determined for 56 caffeine analogs. Replacement of the methyl group at position 3 or 7 resulted in loss of activity, while replacement at position 1 by ethyl or propyl increased activity slightly. 8-Substituted caffeines retained activity, but were relatively insoluble. The structure-activity profile did not resemble those for other known pharmacological activities of caffeine. The active analogs also potentiated the killing of p53-defective cells by ionizing radiation, but none was as effective as caffeine

Se-methylselenocysteine induces apoptosis mediated by reactive oxygen species in HL-60 cells.

Jung U, Zheng X, Yoon SO, et al.

Free Radic Biol Med. 2001 Aug 15; 31(4):479-89.

Recent studies have implicated apoptosis as one of the most plausible mechanisms of the chemopreventive effects of selenium compounds, and reactive oxygen species (ROS) as important mediators in apoptosis induced by various stimuli. In the present study, we demonstrate that Se-methylselenocysteine (MSC), one of the most effective selenium compounds at chemoprevention, induced apoptosis in HL-60 cells and that ROS plays a crucial role in MSC-induced apoptosis. The uptake of MSC by HL-60 cells occurred quite early, reaching the maximum within 1 h. The dose-dependent decrease in cell viability was observed by MSC treatment and was coincident with increased DNA fragmentation and sub-G(1) population. 50 microM of MSC was able to induce apoptosis in 48% of cell population at a 24 h time point. Moreover, the release of cytochrome c from mitochondria and the activation of caspase-3 and caspase-9 were also observed. The measurement of ROS by dichlorofluorescein fluorescence revealed that dose- and time-dependent increase in ROS was induced by MSC. N-acetylcysteine, glutathione, and deferoxamine blocked cell death, DNA fragmentation, and ROS generation induced by MSC. Moreover, N-acetylcysteine effectively blocked caspase-3 activation and the increase of the sub-G(1) population induced by MSC. These results imply that ROS is a critical mediator of the MSC-induced apoptosis in HL-60 cells

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

ARCON: a novel biology-based approach in radiotherapy.

Kaanders JH, Bussink J, van der Kogel AJ.

Lancet Oncol. 2002 Dec; 3(12):728-37.

Two mechanisms of radiotherapy resistance which are of major importance in various tumour types are tumour-cell repopulation and hypoxia. ARCON (accelerated radiotherapy with carbogen and nicotinamide) is a new therapeutic strategy that combines radiation treatment modifications, with the aim of counteracting these resistance mechanisms. To limit clonogenic repopulation during therapy, the overall duration of the radiotherapy is reduced, generally by delivering several fractions per day. This accelerated radiotherapy is combined with inhalation of hyperoxic gas to decrease diffusion-limited hypoxia, and nicotinamide, a vasoactive agent, to decrease perfusion-limited hypoxia. Preclinical studies have been done to test the enhancing effects of these three components of ARCON, individually and in combination, in several experimentally induced tumours and normal tissues. In a mouse mammary carcinoma, the tumour-control rate obtained with ARCON was the same as that with conventional treatment, but with a radiation dose almost 50% lower. Phase 1 and 2 clinical trials have shown the feasibility and tolerability of ARCON, and have produced promising results in terms of tumour control. In particular in cancers of the head and neck and bladder, the local tumour-control rates are higher than in other studies, and phase 3 trials for these tumour types are underway. In conjunction with these trials, hypoxia markers detectable by immunohistochemistry are being tested for their potential use in predictive assays to select patients for ARCON and other hypoxia-modifying therapies

ARCON: experience in 215 patients with advanced head-and-neck cancer.

Kaanders JH, Pop LA, Marres HA, et al.

Int J Radiat Oncol Biol Phys. 2002 Mar 1; 52(3):769-78.

PURPOSE: "ARCON" combines accelerated radiotherapy to counteract tumor repopulation with carbogen breathing and nicotinamide to reduce chronic and acute hypoxia. The aim of this Phase II study was to assess the feasibility, toxicity, and potential effectiveness of ARCON for advanced head-and-neck cancer. METHODS AND MATERIALS: The study included 215 patients with head-and-neck carcinoma distributed as follows: larynx, n = 100; hypopharynx, n = 50; oropharynx, n = 52; oral cavity, n = 13; Stage II, n = 8, Stage III, n = 71, and Stage IV, n = 136. Accelerated radiotherapy was given to a total dose of 64-68 Gy in 2-Gy fractions within 36-38 days. This was combined with carbogen breathing during irradiation and administration of nicotinamide (60-80 mg/kg) 1-1.5 h before irradiation. RESULTS: There was full compliance with carbogen breathing in 88% of the patients. A nicotinamide dose of 80 mg/kg produced severe nausea and vomiting, necessitating discontinuation of the drug, in 31% of the patients. Adjustment of the dose to 60 mg/kg and antiemesis prophylaxis reduced the discontinuation rate to 10%. Confluent mucositis was observed in 91% of the patients with a median duration of 6 weeks. Grade 4 late complications occurred in 5% of the patients. The actuarial 3-year local control rates were 80% for larynx, 69% for hypopharynx, 88% for oropharynx, and 37% for oral cavity tumors. For T3-4 tumors, the local control rates were 80% for larynx, 60% for hypopharynx, 87% for oropharynx, and 29% for oral cavity. Regional control rates were 100% for N0, 93% for N1, and 74% for N2 disease. CONCLUSION: ARCON yields high local and regional control rates in advanced head-and-neck carcinomas, and compliance is satisfactory and morbidity acceptable. The local control rate of 80% for T3 and T4 larynx carcinomas offers excellent possibilities for organ preservation

Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation.

Karbownik M, Reiter RJ.

Proc Soc Exp Biol Med. 2000 Oct; 225(1):9-22.

Ionizing radiation is classified as a potent carcinogen, and its injury to living cells is, to a large extent, due to oxidative stress. The molecule most often reported to be damaged by ionizing radiation is DNA. Hydroxyl radicals (*OH), considered the most damaging of all free radicals generated in organisms, are often responsible for DNA damage caused by ionizing radiation. Melatonin, N-acetyl-5-methoxytryptamine, is a well-known antioxidant that protects DNA, lipids, and proteins from free-radical damage. The indoleamine manifests its antioxidative properties by stimulating the activities of antioxidant enzymes and scavenging free radicals directly or indirectly. Among known antioxidants, melatonin is a highly effective scavenger of *OH. Melatonin is distributed ubiquitously in organisms and, as far as is known, in all cellular compartments, and it quickly passes through all biological membranes. The protective effects of melatonin against oxidative stress caused by ionizing radiation have been documented in in vitro and in vivo studies in different species and in in vitro experiments that used human tissues, as well as when melatonin was given to humans and then tissues collected and subjected to ionizing radiation. The radioprotective effects of melatonin against cellular damage caused by oxidative stress and its low toxicity make this molecule a potential supplement in the treatment or co-treatment in situations where the effects of ionizing radiation are to be minimized

Treatment of erectile dysfunction with sildenafil citrate (Viagra) after radiation therapy for prostate cancer.

Kedia S, Zippe CD, Agarwal A, et al.

Urology. 1999 Aug; 54(2):308-12.

OBJECTIVES: To determine the response to sildenafil citrate (Viagra) in patients with erectile dysfunction after radiation therapy for localized prostate cancer. METHODS: Baseline and follow-up data from 21 patients presenting with erectile dysfunction after radiation treatment for clinical T1-2 prostate cancer were obtained. Two patients had undergone iodine-125 seed implantation and the remaining 19 conformal external beam irradiation. All 21 patients were considered to have erectile dysfunction as assessed by the International Index of Erectile Function (IIEF) and were prescribed sildenafil at a dosage of 50 mg, with a titration to 100 mg if needed. The mean time between the completion of radiation therapy and initiation of sildenafil was 24.6 +/- 5.8 months. The quality of the erectile function was assessed after a minimum of four doses by using the Cleveland Clinic Erectile Function (CCEF) questionnaire and the IIEF questionnaire. A positive response to sildenafil on the CCEF questionnaire was defined as an erection sufficient for vaginal penetration. The responses on the IIEF questionnaire were rated on a scale of 1 (almost never) to 5 (almost always), with 0 being no sexual activity. RESULTS: On the CCEF questionnaire, 71% (15 of 21) of patients had a positive response, with a mean duration of 12.7 +/- 2.5 minutes of intercourse, and a corresponding spousal satisfaction rate of 71%. Twelve (80%) of the 15 responders required titration to the 100-mg dosage for maximal effect. The most common side effects seen were transient flushing (19%), abnormal color vision (14%), and headaches (10%). No patient discontinued the drug because of side effects. On the IIEF questionnaire, the responses to questions 3 (frequency of penetration), 4 (maintenance of erection), 7 (satisfactory intercourse), and 15 (erection confidence) increased from mean baseline scores of 1.3, 1.1, 1.2, and 1.8 to final mean scores of 4.0, 3.9, 3.2, and 3.4, respectively (P <0.001). On the global efficacy question (ability to achieve firm erections), 71% of the patients responded positively. CONCLUSIONS: Sildenafil citrate can improve the ability to achieve and maintain an erection in most patients with erectile dysfunction after radiation therapy for prostate cancer

The use of a whey protein concentrate in the treatment of patients with metastatic carcinoma: a phase I-II clinical study.

Kennedy RS, Konok GP, Bounous G, et al.

Anticancer Res. 1995 Nov; 15(6B):2643-9.

Glutathione (GSH) concentration is high in most tumour cells and this may be an important factor in resistance to chemotherapy. Previous in-vitro and animal experiments have shown a differential response of tumour versus normal cells to various cysteine delivery systems. More specifically, an in-vitro assay showed that at concentrations that induce GSH synthesis in normal human cells, a specially prepared whey protein concentrate, Immunocal, caused GSH depletion and inhibition of proliferation in human breast cancer cells. On the basis of this information five patients with metastatic carcinoma of the breast, one of the pancreas and one of the liver were fed 30 grams of this whey protein concentrate daily for six months. In six patients the blood lymphocyte GSH levels were substantially above normal at the outset, reflecting high tumour GSH levels. Two patients (#1, #3) exhibited signs of tumour regression, normalization of haemoglobin and peripheral lymphocyte counts and a sustained drop of lymphocyte GSH levels towards normal. Two patients (#2, #7) showed stabilisation of the tumour, increased haemoglobin levels. In three patients (#4, #5, #6,) the disease progressed with a trend toward higher lymphocyte GSH levels. These results indicate that whey protein concentrate might deplete tumour cells of GSH and render them more vulnerable to chemotherapy

In vivo radioprotective activity of Panax ginseng and diethyldithiocarbamate.

Kim SH, Cho CK, Yoo SY, et al.

In Vivo. 1993 Sep; 7(5):467-70.

Studies were performed to determine whether the water fraction and the alkaloid fraction of Panax ginseng protect against radiation damage to jejunal crypts of N:GP(s) mice and induction of micronuclei (MN) in cytokinesis-blocked (CB) lymphocytes of C57BL/6 mice after in vivo irradiation with 60Co gamma-rays. The radioprotective effect of ginseng was compared with the effect of diethyldithiocarbamate (DDC). Jejunum was protected by the water fraction (2 mg/ml of drinking water) (P < 0.001) and the alkaloid fraction (5.4 mg/day, P.O.) (P < 0.005), both pre-and post-treatment, and by DDC (1000 mg/kg B.W., single I.P., 30 minutes before 15 Gy irradiation) (P < 0.001). The frequency of radiation (3 Gy)-induced micronuclei in spleen lymphocytes was also reduced by pretreatment of water fraction, alkaloid fraction of ginseng (P < 0.025) and DDC (P < 0.001). The data suggested that the water fraction and alkaloid fraction of Panax ginseng may reduce cell damage caused by gamma-rays, especially damage to DNA molecules, and play a role in the repair or regeneration process of damaged cells

Se-methylselenocysteine induces apoptosis through caspase activation in HL-60 cells.

Kim T, Jung U, Cho DY, et al.

Carcinogenesis. 2001 Apr; 22(4):559-65.

Apoptosis, a programmed process of cell suicide, has been proposed as the most plausible mechanism for the chemopreventive activities of selenocompounds. In our study, we found that Se-methylselenocysteine (MSC) induced apoptosis through caspase activation in human promyelocytic leukemia (HL-60) cells. Measurements of cytotoxicity, DNA fragmentation and apoptotic morphology revealed that MSC was more efficient at inducing apoptosis than selenite, but was less toxic. Moreover, MSC increased both the apoptotic cleavage of poly(ADP-ribose) polymerase (PARP) and caspase-3 activity, whereas selenite did not. We next examined whether caspases and serine proteases are required for the apoptotic induction by MSC. A general caspase inhibitor, z-VAD-fmk, dramatically decreased cytotoxicity in MSC-treated HL-60 cells and several other apoptotic features, such as, caspase-3 activation, the apoptotic DNA ladder, TUNEL-positive staining and the DNA double-strand break. Interestingly, a general serine protease inhibitor, AAPV-cmk, also effectively inhibited MSC-mediated cytotoxicity and apoptosis. These results demonstrate that MSC is a selenocompound that efficiently induces apoptosis in leukemia cells and that proteolytic machinery, in particular caspase-3, is necessary for MSC-induced apoptosis. On the other hand, selenite-induced cell death could be derived from necrosis rather than apoptosis, since selenite did not significantly induce several apoptotic phenomena, including the activation of caspase-3

Protective effect of ginseng on radiation-induced DNA double strand breaks and repair in murine lymphocytes.

Kim TH, Lee YS, Cho CK, et al.

Cancer Biother Radiopharm. 1996 Aug; 11(4):267-72.

We have examined the effects of ginseng on the induction and repair of gamma-ray-induced DNA double strand breaks (dsb) using neutral filter elution technique at pH 9.6 in cultured murine spleen lymphocytes. Ginseng water extract 500 micrograms/ml was added to the culture medium either for 48 hours prior to irradiation. Ginseng extract showed protective effect against the formation of dsb when it was treated for 48 hours before 100 Gy gamma-ray-irradiation. While repair was almost completed until 220.2 minutes after irradiation, DNA repair of irradiated cells in the presence of ginseng extract was did not return to the corresponding control levels even after 621.8 minutes. From these data, it could be calculated that ginseng reduced the relative strand scission factor (RSSF) by about 2. Therefore, it could be concluded that ginseng has radioprotective effect against gamma-ray induced DNA dsb and repair in cultured mouse lymphocytes

Mechanisms involved in the elevation of glutathione in RAW 264.7 cells exposed to low doses of gamma-rays.

Kojima S, Teshima K, Yamaoka K.

Anticancer Res. 2000 May; 20(3A):1589-94.

We examined the mechanisms of the elevation of glutathione level induced in macrophage-like RAW 264.7 cells by low doses of gamma-rays. The level increased soon after exposure of the cells to 50 cGy of gamma-rays, peaked between 3 hours and 6 hours and returned almost to the time 0 value by 24 hours post-irradiation. Doses between 25 and 100 cGy significantly increased the glutathione level at 4 hours post-irradiation. However, there was no significant elevation at doses of more than 100 cGy or less than 25 cGy. When the effect of dose rate was examined at a constant absorbed dose of 50 cGy, dose rates of more than 50 cGy/minute significantly increased the GSH level at 4 hours post-irradiation. It was also shown that the elevation of glutathione level in cells irradiated with low doses of gamma-rays followed the induction of mRNA coding for gamma-glutamylcysteine synthetase (gamma-GCS), a rate-limiting enzyme of the de novo glutathione synthesis pathway. When the cells were exposed to the radiation in the presence of genistein, calphostin C or nifedipine, the elevations of glutathione and gamma-GCS mRNA expression were both mostly blocked. EGTA also strongly inhibited these elevations. These results suggest that the tyrosine kinase, calcium channel and protein kinase C activities play an essential role in the low-dose-radiation-induced elevation of cellular glutathione

D-alpha-tocopheryl succinate (vitamin E) enhances radiation-induced chromosomal damage levels in human cancer cells, but reduces it in normal cells.

Kumar B, Jha MN, Cole WC, et al.

J Am Coll Nutr. 2002 Aug; 21(4):339-43.

OBJECTIVE: The purpose of this study was to measure and compare the effect of d-alpha-tocopheryl succinate (alpha-TS) in modifying radiation-induced chromosomal damage in human normal cells and cancer cells in culture. METHODS: Three human normal fibroblast cell lines (GM2149, AG1522 and HF19) and three human cancer cell lines, cervical cancer (HeLa) and ovarian carcinoma cells (OVGI and SKOV3) were treated with alpha-TS (37.6 microM) 20 hours before 100 cGy gamma-irradiation. After 30 minutes of irradiation, colcemid was added and cells were fixed. One hundred randomly selected metaphase cells were scored for the presence of chromatid gaps and breaks. To study the cellular accumulation of alpha-TS. cells were incubated in the presence of alpha-TS (18.8 and 37.6 microM) for 24 hours, and alpha-TS was extracted with hexane using a-tocopheryl acetate as an internal standard. The levels of alpha-TS were determined by HPLC. RESULTS: Results showed that alpha-TS induced chromosomal damage in both human cervical cancer cells and ovarian cancer cells, but not in human normal fibroblasts in culture. In addition, alpha-TS enhanced the level of radiation-induced chromosomal damage in cancer cells, but it protected normal cells against such damage. Both cancer cells and normal cells accumulated similar levels of alpha-TS, suggesting that increased sensitivity of cancer cells to alpha-TS is acquired during transformation. CONCLUSION: The use of alpha-TS during radiation therapy may improve the efficacy of radiation therapy by enhancing tumor response and decreasing some of the toxicities on normal cells

Striking regression of subcutaneous fibrosis induced by high doses of gamma rays using a combination of pentoxifylline and alpha-tocopherol: an experimental study.

Lefaix JL, Delanian S, Vozenin MC, et al.

Int J Radiat Oncol Biol Phys. 1999 Mar 1; 43(4):839-47.

PURPOSE: To establish a successful treatment of subcutaneous fibrosis developing after high doses of gamma rays, suitable for use in clinical practice. METHODS AND MATERIALS: We used an animal model of acute localized gamma irradiation simulating accidental overexposure in humans. Three groups of 5 Large White pigs were irradiated using a collimated 192Ir source to deliver a single dose of 160 Gy onto the skin surface (100%) of the outer side of the thigh. A well-defined block of necrosis developed within a few weeks which had healed after 26 weeks to leave a block of subcutaneous fibrosis involving skin and skeletal muscle. One experimental group of 5 pigs was dosed orally for 26 weeks starting 26 weeks after irradiation with 1600 mg/120 kg body weight of pentoxifylline (PTX) included in the reconstituted food during its fabrication, and another group of 5 was dosed orally for the same period with a daily dose of 1600 mg/120 kg body weight of PTX combined with 2000 IU/120 kg body weight of alpha-tocopherol. Five irradiated control pigs were given normal food only. Animals were assessed for changes in the density of the palpated fibrotic block and in the dimensions of the projected cutaneous surface. Depth of scar tissue was determined by ultrasound. Physical and sonographic findings were confirmed by autopsy 26 weeks after treatment started. The density, length, width, and depth of the block of fibrotic scar tissue, and the areas and volume of its projected cutaneous surface, were compared before treatment, 6 and 13 weeks thereafter, and at 26 weeks. RESULTS: The experimental animals exhibited no change in behavior and no abnormal clinical or anatomic signs. No modifications were observed in the block of fibrotic scar tissue of pigs dosed with PTX alone. However, significant softening and shrinking of this block were noted in the pigs dosed with PTX + alpha-tocopherol 13 weeks after treatment started and at autopsy, when mean regression was approximately 30% for length, approximately 50% for width and depth, and approximately 70% for area and volume. Histologic examination showed completely normal muscle and subcutaneous tissue surrounding the residual scar tissue. The 50% decrease in the linear dimensions of the scar tissue, were comparable to the results obtained in our previous clinical studies, and were highly significant compared to the clinical and autopsy results for the controls. Histologic examination of the residual scar tissue revealed tissue which was more homogenous and less cellular and inflammatory than in control and PTX-dosed pigs. The tissular and cellular immunolocalization of tumor necrosis factor alpha (TNFalpha) was similar in the residual fibrotic tissues of all three groups of pigs, whereas the immunostaining of transforming growth factor beta-1(TGFbeta-1) diminished much more in the residual fibrotic scar tissue of the PTX + alpha-tocopherol-dosed pigs than in the two other groups. CONCLUSIONS: The present results showed a striking regression of the subcutaneous fibrotic scar tissue that develops as a consequence of high doses of gamma rays

Oral vitamin a therapy for a patient with a severely symptomatic postradiation anal ulceration: report of a case.

Levitsky J, Hong JJ, Jani AB, et al.

Dis Colon Rectum. 2003 May; 46(5):679-82.

Squamous-cell carcinoma of the anus is an uncommon but treatable gastrointestinal malignancy. Radiation, in addition to chemotherapy, is widely accepted as the standard of care for treatment in most patients. However, significant anal complications, such as stricture, fistula, and ulceration, may result from radiation therapy. Some medical therapies have been used for radiation proctopathy, but treatments for radiation-induced anal injury other than surgical diversion are unknown. Vitamin A has been shown in laboratory studies to facilitate wound healing and prevent radiation-induced gastrointestinal damage. However, it has not been used clinically in patients with radiation enteritis, proctopathy, or anal ulceration. We report a case of a patient with human immunodeficiency virus infection who developed a symptomatic anal ulcer after receiving high-dose radiotherapy for anal squamous-cell carcinoma. We prescribed 8,000 IU of oral vitamin A twice daily and within seven weeks his anorectal symptoms and anal ulcer completely resolved. Vitamin A seems to be very effective in the treatment of radiation-induced anorectal damage, with little toxicity and expense

Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone.

Lissoni P, Meregalli S, Nosetto L, et al.

Oncology. 1996 Jan; 53(1):43-6.

The prognosis of brain glioblastoma is still very poor and the median survival time is generally less than 6 months. At present, no chemotherapy has appeared to influence its prognosis. On the other hand, recent advances in brain tumor biology have suggested that brain tumor growth is at least in part under a neuroendocrine control, mainly realized by opioid peptides and pineal substances. On this basis, we evaluated the influence of a concomitant administration of the pineal hormone melatonin (MLT) in patients with glioblastoma treated with radical or adjuvant radiotherapy (RT). The study included 30 patients with glioblastoma, who were randomized to receive RT alone (60 Gy) or RT plus MLT (20 mg/daily orally) until disease progression. Both the survival curve and the percent of survival at 1 year were significantly higher in patients treated with RT plus MLT than in those receiving RT alone (6/14 vs. 1/16). Moreover, RT or steroid therapy-related toxicities were lower in patients concomitantly treated with MLT. This preliminary study suggests that a radioneuroendocrine approach with RT plus the pineal hormone MLT may prolong the survival time and improve the quality of life of patients affected by glioblastoma

Reversal of clinical resistance to LHRH analogue in metastatic prostate cancer by the pineal hormone melatonin: efficacy of LHRH analogue plus melatonin in patients progressing on LHRH analogue alone.

Lissoni P, Cazzaniga M, Tancini G, et al.

Eur Urol. 1997; 31(2):178-81.

OBJECTIVE: Experimental and preliminary clinical studies have suggested that the pineal hormone melatonin (MLT) may stimulate hormone receptor expression on both normal and cancer cells. Moreover, MLT has appeared to inhibit the growth of some cancer cell lines, including prostate cancer, either by exerting a direct cytostatic action, or by decreasing the endogenous production of some tumor growth factors, such as prolactin (PRL) and insulin-like growth factor-1 (IGF-1). On this basis, a study was carried out to evaluate the clinical efficacy of a neuroendocrine combination consisting of the LHRH analogue triptorelin plus MLT in metastatic prostate cancer progressing on triptorelin alone. MATERIAL AND METHODS: The study including 14 consecutive metastatic prostate cancer patients with poor clinical conditions (median age: 70.5 years; median PS: 50%), refractory or resistant to a previous therapy with the LHRH analogue triptorelin alone. Triptorelin was injected i.m. at 3.75 mg every 28 days, and MLT was given orally at 20 mg/day in the evening every day until progression, starting 7 days prior to triptorelin. RESULTS AND CONCLUSIONS: A decrease in PSA serum levels greater than 50% was obtained in 8/14 (57%) patients. Moreover, PSA mean concentrations significantly decreased on therapy of triptorelin plus MLT. In addition, a normalization of platelet number was obtained in 3/5 patients with persistent thrombocytopenia prior to study. Mean serum levels of both PRL and IGF-1 significantly decreased on therapy. Finally, a survival longer than 1 year was achieved in 9/14 (64%) patients. This preliminary study would suggest that the concomitant administration of the pineal hormone MLT may overcome the clinical resistance to LHRH analogues and improve the clinical conditions in metastatic prostatic cancer patients

Thrombopoietic properties of 5-methoxytryptamine plus melatonin versus melatonin alone in the treatment of cancer-related thrombocytopenia.

Lissoni P, Bucovec R, Bonfanti A, et al.

J Pineal Res. 2001 Mar; 30(2):123-6.

Recent studies have shown that the hematopoietic system is under neuroendocrine control. In particular, thrombopoiesis has been proven to be stimulated by melatonin, and the pineal indole has been shown to be effective in the treatment of thrombocytopenia resulting from different causes. At present, however, there are no data concerning the possible thrombopoietic activity of pineal indoles other than melatonin. The present study was carried out to evaluate the effect of a concomitant administration of the pineal indole 5-methoxytryptamine in patients with cancer-related thrombocytopenia who did not respond to melatonin alone. The present study included 30 patients, who were randomized to receive melatonin alone (20 mg/day orally in the evening) or melatonin plus 5-methoxytryptamine (1 mg/day orally in the early afternoon). A normalization of platelet count was achieved in 5/14 (36%) patients treated with melatonin plus 5-methoxytryptamine and in none of the patients treated with melatonin alone (P < 0.05). Moreover, mean platelet number significantly increased only in the patients treated with melatonin plus 5-methoxytryptamine. This preliminary clinical study would suggest that 5-methoxytryptamine, a pineal indole, may also exert thrombopoietic activity. Further studies, however, will be required to establish whether 5-methoxytryptamine may play a direct thrombopoietic activity, or whether it may act by improving melatonin's efficacy

Effects of oral administration of tea, decaffeinated tea, and caffeine on the formation and growth of tumors in high-risk SKH-1 mice previously treated with ultraviolet B light.

Lou YR, Lu YP, Xie JG, et al.

Nutr Cancer. 1999; 33(2):146-53.

Treatment of SKH-1 mice with ultraviolet B light (UV-B, 30 mJ/cm2) twice a week for 22-23 weeks resulted in tumor-free animals with a high risk of developing malignant and nonmalignant tumors during the next several months in the absence of further UV-B treatment (high-risk mice). In three separate experiments, oral administration of green tea or black tea (4-6 mg tea solids/ml) as the sole source of drinking fluid for 18-23 weeks to these high-risk mice inhibited the formation and decreased the size of nonmalignant squamous cell papillomas and keratoacanthomas as well as the formation and size of malignant squamous cell carcinomas. In one experiment all these inhibitory effects of tea were statistically significant, whereas in the two other experiments many but not all of the inhibitory effects of tea were statistically significant. The decaffeinated teas were inactive or less effective inhibitors of tumor formation than the regular teas, and adding caffeine back to the decaffeinated teas restored biological activity. Oral administration of caffeine alone (0.44 mg/ml) as the sole source of drinking fluid for 18-23 weeks inhibited the formation of nonmalignant and malignant tumors, and this treatment also decreased tumor size in these high-risk mice

Se-methylselenocysteine: a new compound for chemoprevention of breast cancer.

Medina D, Thompson H, Ganther H, et al.

Nutr Cancer. 2001; 40(1):12-7.

Selenium compounds have attracted renewed interest as chemopreventive agents for human cancer on the basis of the pioneering intervention study by Clark and co-workers. The rodent mammary gland has been used extensively as a model for examining the chemopreventive activities of inorganic and organic selenium compounds. This review summarizes the rationale and results for use of a new organic selenium compound, Se-methylselenocysteine, which exhibits greater efficacy as a chemopreventive agent than several previously used selenium compounds in experimental models of breast cancer and has potential for use in human populations

Effects of caffeine as an adjuvant to morphine in advanced cancer patients. A randomized, double-blind, placebo-controlled, crossover study.

Mercadante S, Serretta R, Casuccio A.

J Pain Symptom Manage. 2001 May; 21(5):369-72.

Psychomotor abnormalities are one of the complications of opioid therapy in advanced cancer patients. Caffeine has potential properties to counteract the central effects of morphine. Twelve patients receiving stable doses of slow release morphine with adequate pain relief were scheduled for this double-blind placebo-controlled crossover trial. The treatment consisted of an intravenous dose of 1/6 of the daily morphine dose, using an intravenous/oral conversion ratio of 1:3. The dose calculated was administered in 5 minutes. Patients were randomly divided to received in a double-blind manner an infusion of 200 mg of caffeine or saline solution intravenously over one hour. A crossover took place after 2-3 days. Patients were assessed immediately before the infusion and once at the end (one hour after). Each assessment included pain, nausea, confusion, and drowsiness intensity. Psychomotor tests, including tapping speed with 10-30 seconds trials, arithmetic tests, memory for digits, and visual memory were also performed. Caffeine infusion induced a significant decrease in pain intensity (from 25.3 to 16.3, p =0.003), but this was no different from the placebo. Caffeine increased both tapping speed tests (p = 0.041 and 0.010, respectively) in comparison with placebo treatment. No other significant differences were found in the other parameters examined. Caffeine showed a partial effect on the cognitive performance of advanced cancer patients on chronic morphine treatment who received a bolus of intravenous morphine. Further studies are necessary to evaluate whether higher doses of caffeine may be more effective and to establish the role of tolerance to caffeine in this group of patients

Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation.

Mukhopadhyay D, Tsiokas L, Zhou XM, et al.

Nature. 1995 Jun 15; 375(6532):577-81.

Angiogenesis, the formation of new microvasculature by capillary sprouting, is crucial for tumour development. Hypoxic regions of solid tumours produce the powerful and directly acting angiogenic protein VEGF/VPF (vascular endothelial growth factor/vascular permeability factor). We now investigate the signal transduction pathway involved in hypoxic induction of VEGF expression. Hypoxia is known to induce a tyrosine kinase cascade that results in the activation of nitrogen-fixation genes in Rhizobium meliloti, and activation of tyrosine kinases is critical in signalling triggered by growth factors and ultraviolet light. We show here that genistein, an inhibitor of protein tyrosine kinase, blocks VEGF induction. Hypoxia increases the kinase activity of pp60c-src and its phosphorylation on tyrosine 416 but does not activate Fyn or Yes. Expression of either a dominant-negative mutant form of c-Src or of Raf-1 markedly reduces VEGF induction. VEGF induction by hypoxia in c-src(-) cells is impaired, although there is a compensatory activation of Fyn. Our results provide an insight into hypoxia-triggered intracellular signalling, define VEGF as a new downstream target for c-SRC, and suggest a role for c-SRc in promoting angiogenesis

Nitric oxide modulates capillary formation at the endothelial cell-tumor cell interface.

Phillips PG, Birnby LM, Narendran A, et al.

Am J Physiol Lung Cell Mol Physiol. 2001 Jul; 281(1):L278-L290.

Nitric oxide synthase expression has been documented in lung tumors, but a potential role for nitric oxide (NO) in induction of capillary formation remains to be elucidated. The purpose of this report was to characterize the direct effects of NO at the level of the tumor-endothelium interface with respect to angiogenesis. A Transwell two-compartment culture system, human endothelial cells (EC), and two human non-small cell lung cancer (CA) lines that constitutively produce NO were used to simulate the EC-tumor cell interface. Both histological types of lung CA, squamous and adenocarcinoma, induced baseline capillary formation by EC within 3 days. This process was inhibited by NO in the microenvironment because decreasing NO production with 100 microM aminoguanidine (AG) significantly increased capi