Recent studies from our laboratory have demonstrated that dietary supplemental calcium had no significant effect on the incidence of 1,2-dimethylhydrazine-induced colonic tumors, but did decrease the number of rats with multiple tumors and reduced tumor size. Moreover, concomitant vitamin D deficiency appeared to abolish these protective effects of calcium on colonic tumors in this experimental model. To date, however, the mechanism(s) involved in these phenomena remain unclear.

In order to address these important issues, 1,2-dimethylhydrazine-induced colonic tumors from animals on control, Ca2+-supplemented, vitamin D-sufficient, and Ca2+-supplemented, vitamin D-deficient diets were examined for the presence of ras oncogene mutations. DNA was extracted from each of these tumors. Targeted areas of K-ras and H-ras genes were amplified by the polymerase chain reaction and analyzed for point mutations using allele-specific oligonucleotide hybridization and subsequent DNA sequencing.

The results of these studies demonstrated that: (a) ∼ one-third of 1,2-dimethylhydrazine-induced colonic carcinomas in the control group had K-ras G to A mutations; (b) no mutations, however, were detected in the cancers of the calcium-supplemented group; (c) concomitant vitamin D deficiency abolished the antimutagenic effect of dietary calcium supplementation (e.g., ∼ one-third of cancers in this group again had detectable K-ras mutations); and (d) no H-ras point mutations were detected in colonic tumors from any group. These findings suggest that alterations in K-ras mutations may be one possible mechanism by which calcium and vitamin D status influence colonic carcinogenesis in this experimental model.

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This investigation was supported by Grant CA36745 from the National Cancer Institute; Digestive Disease Research Center Grant DK42086 from the National Institutes of Diabetes and Digestive and Kidney Diseases; Grants HL 38180 and KO-4 HL 02166 from the Heart, Lung, and Blood Institutes; Clinical Nutrition Research Unit Grant DK 26678; and the Samuel Freedman Research Laboratories for Gastrointestinal Research. T. A. B. is the recipient of a Merit Award from the National Cancer Institute, NIH.

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