Rigorous testing of the efficacy of dietary patterns and nutritional components in colon cancer prevention in humans has been extremely limited by practical constraints. Using colonic neoplasms as endpoints in clinical trials requires extremely large sample sizes, prolonged follow-up, or both. In addition, maintaining prolonged complex dietary interventions in clinical trials is difficult. Animal experimental evidence and exciting preliminary evidence in humans strongly suggests that hyperproliferation of colonic crypt epithelial cells is a biomarker or precursor lesion for colonic neoplasia and that this hyperproliferation can be reversed by nutritional intervention and the risk of colonic cancer thereby reduced. Limited flawed information is available regarding the relation of colonic epithelial cell proliferation (CECP) to colonic neoplasia in humans and is restricted to CECP measurement using tritiated thymidine labeling of S-phase cells. This procedure and its unvalidated successor, 5-bromodeoxyuridine (BrdU) labeling of S-phase cells, are not feasible for use in full-scale human intervention trials. We have now adapted the more reliable and feasible proliferating cell nuclear antigen (PCNA) and whole crypt mitotic count (WCMC) techniques of measuring CECP. Since earlier validation studies used a technique not suitable for large scale clinical trials and were, as we now know, inadequate studies on which to justify large scale clinical trials, we propose to evaluate more properly the relationship of CECP to risk of colon neoplasia in humans and to do so using the newer techniques (PCNA and WCMC). We propose to do this by the financially and technically efficient expedient of extending and modifying our current case-control study of colonic polyps. In the current case-control study, patients going to colonoscopy complete questionnaires on colon cancer risk factors such as diet, nutritional supplement intake, family history, etc. Patients also have blood drawn for lipid profiles and DNA for acetyltransferase and APC genotypes. Incident adenoma patients are cases, and patients with normal colonoscopies and without a history of colonic neoplasms are controls. We propose to obtain rectal, sigmoid, and proximal colon mucosal biopsies at these usual-care colonoscopies and from these determine CECP by both the PCNA and WCMC techniques. From this information, we will establish interrelationships among colon neoplasia risk factors (especially dietary), CECP, and colon neoplasia; whether or not CECP levels measured on a rectal biopsy reflects levels throughout the colon; whether CECP measured by the PCNA or the WCMC techniques or a combination of the two provides greater discriminatory power in distinguishing levels and causes of increased risk of neoplasia; and whether the PCNA or the WCMC technique is more reliable and/or feasible for application to full-scale dietary/chemoprevention trials.
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