Project: Research project

Project Details


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
Effective start/end date1/1/9112/31/94


  • National Institutes of Health


  • Medicine(all)


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