S27. Prevention of colorectal polyps by DMFO and Sulindac

摘要

Polyamines are actively involved in proliferation and differentiation of many tissues. Lowering of intracellular levels via inhibition of the initial step (ornithine decarboxylase) in the polyamine synthesis pathway by the specific enzyme-activated inhibitor difiuoromethyl-ornithine (DFMO) results in a decrease of adenomas and cancers in many preclinical organ-site models, most notable in the colon. From 1989-1997 we conducted a series of pilot, Phase Ha and Phase lib trials. We determined the lowest dose at which polyamine content of the colonic flat mucosa would be significantly lowered. In 1997 we considered whether to do a definitive trial with DFMO alone or to combine it with another chemopreventive compound. We decided to combine DFMO with the NSAID Sulindac at a low dose for a variety of mechanistic, experimental, and clinical reasons.