The multi-step process of colon carcinogenesis as observed in other organs like the skin and liver is operationally defined into stages of initiation, promotion, and progression. Calcium has been shown in an increasing number of studies in rodent and n to be an active chemoprevention agent. Where animal calcium chemoprevention models depart significantly from that in man is within the conceptual framework of carcinogenesis. In man subjects with resected colonic adenoma, a defined premalignant lesion, or, familial risk of colon cancer, consume supplemental calcium and effects are observed on the recurrence of the adenoma/adenocarcinoma and/or intermediate biomarkers of mucosal proliferation. Since a premalignancy was established, human interventions occur in the """"""""progression"""""""" phase of carcinogenesis. This application addresses the need for a relevant animal model for colon cancer progression for purposes of comparing the effect of calcium in this phase versus initiation and promotion. Using a short induction period with the colon carcinogen, azoxymethane, F344 rats will be fed a standard AIN-76A diet plus 0.5% cholic acid, a regimen markedly increases the propensity of adenoma in the rat colon. A model for adenoma induction will be established and the progression phase defined. During the experiment intermediate markers of colonic proliferation, including tritiated thymidine uptake, bromodeoxyuridine immunoperoxidase labeling, ornithine decarboxylase activity and protein kinase C activity, will be measured and correlated with tumor progression. In the second part of the project using the defined progression model, calcium supplementation (using an effective dose established by short modulation of intermediate biomarkers) will be tested for a suppressing effect separately in each of the operational phases of colon carcinogenesis along with observations on intermediate biomarker response to calcium. The proposed model will immeasurably add to the biological recognition of the three phases of multi-step colon carcinogenesis; the reproducibility of the model will allow for future characterization of the cardinal biochemical, cellular, and molecular hallmarks of each stage in a more precisely defined animal model for colon cancer.
| Kuratko, C N; Pence, B C (1995) Dietary lipid and iron modify normal colonic mucosa without affecting phospholipase A2 activity. Cancer Lett 95:181-7 |
| Pence, B C; Dunn, D M; Zhao, C et al. (1995) Chemopreventive effects of calcium but not aspirin supplementation in cholic acid-promoted colon carcinogenesis: correlation with intermediate endpoints. Carcinogenesis 16:757-65 |
