Combination chemoprevention for colon cancer targeting polyamine synthesis and inflammation

Abstract

Increased polyamine synthesis and inflammation have long been associated withcoloncarcinogenesis in both preclinical models and in humans. Recent experimental studies suggest thatpolyamines may be mechanistically involved in colonic inflammatory processes. Genetic epidemiologyresults indicate that a single nucleotide polymorphism influencing the expression of apolyaminebiosynthetic gene is associated with both risk of colon polyp occurrence and recurrence, andthe response to aspirin as a polyp preventive agent. A prospective, randomized, placebo-controlled clinical trial ofcombination difluoromethylornithine, a selective inhibitor of polyamine synthesis, and sulindac,anonsteroidal anti-inflammatory drug, found that the 3-year treatment was associated with a 70%reduction of recurrence of all adenomas, and over a 90% reduction of recurrence of advanced and/ormultipleadenomas, without evidence of serious toxicities. This proof-of-principle trial indicates thattargeting polyamine synthesis and inflammation can be an effective strategy for preventing the occurrence of theadvanced and/or multiple adenomas that are most closely associated with the development of coloncancers in humans. © 2009 American Association for Cancer Research.