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1,25-(OH)₂-D₃ and Its Synthetic Analogue Decrease Tumor Load in the Apc^min Mouse¹

University of California-Los Angeles Center for Human Nutrition, Los Angeles, California 90095 [S. H., R. W. I., D. H., V. L. W. G., D. M. H.]; Division of Hematology-Oncology, Cedars-Sinai Medical Center/University of California-Los Angeles School of Medicine, Los Angeles, California 90048 [H. P. K.]; Hoffmann-LaRoche Inc., Nutley, New Jersey 07110 [M. R. U.]

Both calcium and vitamin D are thought to be able to inhibit colon carcinogenesis. To better define the effects of vitamin D, we studied 1,25-(OH)₂-D₃ and a noncalcemic synthetic analogue of vitamin D₃ (VD₃) in the Apc^min mouse. Female Apc^min mice 4–5 weeks old were randomized to four groups: a VD₃-treated group (n = 11) were given injections of 0.01 µg of 1,25-(OH)₂-D₃ i.p. three times per week; an analogue-treated group (n = 10) received 5 µg of 1,25-(OH)₂-16-ene-19-nor-24-oxo-D₃ i.p. three times per week; and a control group (n = 12) received sham injections of PBS. A sulindac-treated group (n = 10) was used as a positive control. Doses of these compounds were chosen based on previous toxicity studies in mice and rats. After 10 weeks of treatment, mice were killed and two observers (S. H., R. W. I.), blinded to treatment, scored polyp number and size. Tumor number was not affected with 1,25-(OH)₂-D₃ or vitamin D analogue administration. A significant decrease in total tumor load (sum of all polyp areas) over the entire gastrointestinal tract was seen in the analogue (36% decrease; P < 0.05) and the VD₃ groups (46%; P < 0.001). There was a significant decrease in polyp number (49%; P < 0.001) and polyp area (70%; P < 0.001) in the sulindac group. Reverse transcription-PCR of the total RNA derived from intestinal tissue revealed expression of the vitamin D receptor throughout the small intestine and the colon. Serum calcium levels in the analogue group were not elevated at week 4 of treatment and only moderately elevated (22%) by week 8 (P 0.001). In contrast, serum calcium in the VD₃ group was significantly elevated (P 0.001) at weeks 4 (23%) and 8 (45%). Food intake and growth rate were significantly lower in the VD₃ group (26%, P < 0.001, and 27%, P < 0.001, respectively) at week 10. In contrast, food intake and growth rate were similar for the control, sulindac, and analogue groups. Our results indicate that a noncalcemic analogue of vitamin D can significantly decrease intestinal tumor load in Apc^min mice without severe toxic side effects and suggest that these compounds may have utility as chemopreventive agents in groups at high-risk for colon cancer.

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