1α,25-(OH)2-D3 and its synthetic analogue decrease tumor load in the Apcmin mouse

Sergio Huerta, Ronald W. Irwin, David Heber, Vay Liang W Go, H. Phillip Koeffler, Milan R. Uskokovic, Diane M. Harris

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92 Scopus citations

Abstract

Both calcium and vitamin D are thought to be able to inhibit colon carcinogenesis. To better define the effects of vitamin D, we studied 1α,25-(OH)2-D3 and a noncalcemic synthetic analogue of vitamin D3 (VD3) in the Apcmin mouse. Female Apcmin mice 4-5 weeks old were randomized to four groups: a VD3-treated group (n = 11) were given injections of 0.01 μg of 1α,25-(OH)2-D3 i.p. three times per week; an analogue-treated group (n = 10) received 5 μg of 1α,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 1α,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 Apcmin 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.

Original languageEnglish (US)
Pages (from-to)741-746
Number of pages6
JournalCancer research
Volume62
Issue number3
StatePublished - Feb 1 2002

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Huerta, S., Irwin, R. W., Heber, D., Go, V. L. W., Koeffler, H. P., Uskokovic, M. R., & Harris, D. M. (2002). 1α,25-(OH)2-D3 and its synthetic analogue decrease tumor load in the Apcmin mouse. Cancer research, 62(3), 741-746.