This application, a resubmission for the renewal of """"""""Calcium Prevention of Neoplastic Polyps,"""""""" is a proposal to collect further information on subjects in our randomized, placebo-controlled trial of calcium supplementation for the prevention of colorectal adenomas. The study began in response to animal and human experimental data and some epidemiological findings suggesting that calcium intake may exert a protective effect on large bowel neoplasia. The trial studied whether supplementation with calcium carbonate (1200 mg calcium per day) prevented the recurrence of colorectal adenomas in 930 patients with a recent history of these tumors. Treatment in the trial ended in December, 1996. Calcium lowered the risk of any recurrent adenoma by 18% (95% CI 0.66-0.98), and reduced the number of adenomas by 25% (95% CI 0.55-0.94). We now propose to investigate whether the effect of calcium persisted beyond active treatment, or if there was a subsequent rebound. We also plan to study some related biological mechanisms. Studies of calcium supplementation and mucosal proliferation in the bowel have been conflicting, but the relationship between calcium intake and apoptosis has been investigated and merits study. Further evidence that dietary calcium may preferentially affect the risk of adenomas harboring ras mutations needs confirmation. As well, animal models and some epidemiological data suggest that vitamin D may protect against bowel carcinogenesis. We propose to investigate this in the context of our trial, and to examine polymorphisms in the vitamin D receptor gene. With the funds requested here, we will use our established subject population and available biological specimens to study these mechanisms. We will follow the subjects in the study until the year 2003, monitor their medical history, and track adenoma recurrence after the end of treatment in the trial. All subjects provided blood specimens at study entry and at study exit. Using these samples, we will measure 25-OH vitamin D and 1,25-OH vitamin D to document how calcium supplementation affected these levels, and how the baseline levels and polymorphisms in the vitamin D receptor related to adenoma occurrence. We will also obtain slides from each adenoma detected during the risk period of the trial or during the additional follow-up period and investigate the association between calcium treatment and ras mutation. Finally, we propose to conduct a pilot study in preparation for a study of calcium supplementation and apoptosis both in normal rectal mucosa and in adenomas.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
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Subcommittee G - Education (NCI)
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Malone, Winfred F
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Dartmouth College
Internal Medicine/Medicine
Schools of Medicine
United States
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