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 explain how sulindac restores normal growth patterns. A few clinical observations and an abundance of experimental data can be integrated to produce a reasonable model based on current biochemical and physiologic concepts. A fundamental defect in the formation of colon polyps is mutation of the APC (adenomatous polyposis coli) gene that leads to inadequate suppression of proliferation. There is high PGE2 content in colon polyps and cancers, presumably the result of stimulation by protein kinase C (PKC). In small quantities it stimulates cyclic AMP production but with persistent high concentrations it desensitizes and down-regulates specific PG receptors and inactivates adenylate cyclase, cAMP synthesis, and the cAMP-dependent mechanism for control of proliferation. The PKC pathway is thereby unopposed. It is hypothesized that restriction of PG synthesis by sulindac is accompanied by resensitization 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 inadequate mutant APC suppressor gene to one sufficient to inhibit colon polyp formation.
Waddell
W R
WR
Department of Surgery, University of Colorado, Denver.
D003110:Colonic Neoplasms / Q000378:metabolism; D003111:Colonic Polyps / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D017491:Genes, APC; D006801:Humans; D010641:Phenotype; D011982:Receptors, Prostaglandin / Q000378:metabolism; D013467:Sulindac / Q000627:therapeutic use*
D011982:Receptors, Prostaglandin; D013467:Sulindac; D015232:Dinoprostone