THE EFFECT OF SULINDAC ON COLON POLYPS - CIRCUMVENTION OF A TRANSFORMED PHENOTYPE - A HYPOTHESIS

Sulindac suppresses the growth of colon polyps in Gardner syndrome and familial adenomatous polyposis. The mechanism of action is not known. The problems are to ascertain the significance of high prostaglandin concentrations in transformed cells, colon polyps and cancers and to e xplain how sulindac restores normal growth patterns. A few clinical ob servations and an abundance of experimental data can be integrated to produce a reasonable model based on current biochemical and physiologi c concepts. A fundamental defect in the formation of colon polyps is m utation of the APC (adenomatous polyposis coli) gene that leads to ina dequate suppression of proliferation. There is high PGE(2) content in colon polyps and cancers, presumably the result of stimulation by prot ein kinase C (PKC). In small quantities it stimulates cyclic AMP produ ction but with persistent high concentrations it desensitizes and down -regulates specific PG receptors and inactivates adenylate cyclase, cA MP synthesis, and the cAMP-dependent mechanism for control of prolifer ation. The PKC pathway is thereby unopposed. It is hypothesized that r estriction of PG synthesis by sulindac is accompanied by resensitizati on of PG receptors, and reactivation of the cAMP-dependent pathway for control of cell growth. It is further postulated that restoration of cAMP synthesis and protein kinase A activity converts a functionally i nadequate mutant APC suppressor gene to one sufficient to inhibit colo n polyp formation. (C) 1994 Wiley-Liss, Inc.