Human feces has been found to contain a group of highly mutagenic compounds called fecapentaenes. These compounds produce a variety of genotoxic effects. They are direct acting mutagens, increase DNA synthesis in rat hepatocytes, induce neoplastic transformation in mouse BALB/c3T3 cells and cause DNA single strand breaks, sister chromatid exchanges and mutations in human fibroblasts. The above findings suggest that a major factor in the causation of cancer of the large bowel in the human may have been found. However, thus far, a successful demonstration of fecapentaene-induced carcinogenesis in vivo has not been accomplished. Major problems that could account for these negative results have been defective handling of the fecapentaenes which are very labile compounds; inappropriate solvents; and inadequate animal models. The primary objective of the present proposal is to determine if fecapentaenes can produce a full or partial neoplastic response in the mucosa of the large bowel in experimental animals. Methodology for preventing decomposition of the fecapentaene will be employed. Short-term in vivo test systems will be used to determine the solvent, delivery conditions and dose schedule most likely to result in a carcinogenic response. These include assessment of expansion of the proliferative compartment of the crypts of the large bowel, determination of the presence of increased mitotic activity, studies of formation of nuclear aberrations, and studies of formation of aberrant crypts. Employing optimal conditions ascertained from the above, carcinogenesis studies will be undertaken to determine if fecapentaene: (1) is a full carcinogen, (2) is a tumor initiator, (3) is a tumor promoter, (4) can cause tumor progression, and/or (5) has syncarcinogenic properties in the mucosa of the large bowel. If positive results are obtained, they could form a basis evaluating the carcinogenic hazard from fecapentaenes and means of its prevention.
