Animal Models for Colon Cancer Chemoprevention. Encyclopedia of Cancer, Second Edition Elsevier Science (USA). Volume 1

Colorectal cancer is a tumor of colon and rectum, which occurs with high frequency in both men and women in Western countries. Most cases of colorectal cancers arise in a benign adenoma; some evidence suggests that some cancers arise directly from the mucosal cells. With regard to genetic mechanisms of colorectal cancer, the disease appears to result from an increase in the number of genetic mutations, mostly acquired, that accumulate in the genome of the evolving cancer cell.

The pineal neurohormone melatonin synchronizes functionally the organism with the photoperiod. It is now well recognized that melatonin also plays an important immunoregulatory role. T-helper cells bear G-protein coupled melatonin cell membrane receptors and, perhaps, melatonin nuclear receptors. Activation of melatonin receptors enhances the release of T-helper cell type 1 (Th1) cytokines, such as g-interferon and interleukin-2, as well as of novel opioid cytokines which crossreact immunologically with both interleukin-4 and dynorphin B. Melatonin has been reported also to enhance the production of interleukin-6 from human monocytes. These mediators may counteract secondary immunodeficiences, protect mice against lethal viral and bacterial diseases, synergize with interleukin-2 in cancer patients and influence hematopoiesis. Hematopoiesis is apparently influenced by the action of the melatonin-induced-opioids on kappa-opioid receptors present on stromal bone marrow cells. Most interestingly, g-interferon and colony stimulating factors may modulate the production of melatonin in the pineal gland. A hypothetical pineal-immune-hematopoietic network is, therefore, taking shape. From the immunopharmacological point of view, a call is made for clinical studies on the effect of melatonin in viral disease including human immunodeficiency virus-infected patients and cancer patients. In conclusion, melatonin seems to be an important immunomodulatory hormone which deserves to be further studied to identify its relevance in immune-based diseases, its therapeutic indications and its adverse effects.

Melatonin suppresses AOM/DSS-induced large bowel oncogenesis in rats
The inhibitory effects of exogenous melatonin (MEL) on colon oncogenesis were investigated using an azoxymethane (AOM)/dextran sodium sulfate (DSS) rat model. Male F344 rats initiated with a single intraperitoneal injection of AOM (20 mg/kg bw) were promoted by 1% (w/v) DSS in drinking water for 7 days. They were then given 0.4, 2 or 10 ppm MEL in drinking water for 17 weeks. At week 20, the development of colonic adenocarcinoma was significantly inhibited by the administration with MEL dose-dependently. MEL exposure modulated the mitotic and apoptotic indices in the colonic adenocarcinomas that developed and lowered the immunohistochemical expression of nuclear factor kappa B, tumor necrosis factor α, interleukin-1β and STAT3 in the epithelial malignancies. These results may indicate the beneficial effects of MEL on colitis-related colon carcinogenesis and a potential application for inhibiting colorectal cancer development in the inflamed colon.
Tanaka T, Yasui Y, Tanaka M, et al. Chemico-Biological Interactions. Volume 177, Issue 2, 27 January 2009, Pages 128-36. doi:10.1016/j.cbi.2008.10.047

The inhibitory effects of mangiferin, a naturally occurring glucosylxanthone, in bowel carcinogenesis of male F344 rats
Mangiferin, 1,3,6,7-tetrahydroxyxanthone-C2-beta-Image -glucoside, is one of xanthone derivatives and C-glucosylxanthones, is widely distributed in higher plants and is one of constituents of folk medicines. Recent studies showed that mangiferin has a potential as an anti-oxidant and an anti-viral agent. In this study, we examined the effects of mangiferin in rat colon carcinogenesis induced by chemical carcinogen, azoxymethane (AOM). We performed two experiments: a short-term assay to investigate the effects of mangiferin on the development of preneoplastic lesions by AOM, aberrant crypt foci (ACF), and the following long-term assay for the influence of mangiferin on tumorigenesis induced by AOM. In the short-term assay, 0.1% mangiferin in a diet significantly inhibited the ACF development in rats treated with AOM compared to rats treated with AOM alone (64.6±22.0 vs. 108.3±43.0). In the long-term assay, the group treated with 0.1% mangiferin in initiation phase of the experimental protocol had significantly lower incidence and multiplicity of intestinal neoplasms induced by AOM (47.3 and 41.8% reductions of the group treated with AOM alone for incidence and multiplicity, respectively). In addition, the cell proliferation in colonic mucosa was reduced in rats treated with mangiferin (65–85% reductions of the group treated with AOM alone). These results suggest that mangiferin has potential as a naturally-occurring chemopreventive agent.
Yoshimi N, Matsunaga K, Katayama M, et al. Cancer Letters. Volume 163, Issue 2, 26 February 2001, Pp. 163-70 doi:10.1016/S0304-3835(00)00678-9

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