Combination chemoprevention for colon cancer targeting polyamine synthesis and inflammation.
Increased polyamine synthesis and inflammation have long been associated with colon carcinogenesis in both preclinical models and in humans. Recent experimental studies suggest that polyamines may be mechanistically involved in colonic inflammatory processes. Genetic epidemiology results indicate that a single nucleotide polymorphism influencing the expression of a polyamine biosynthetic gene is associated with both risk of colon polyp occurrence and recurrence, and the response to aspirin as a polyp preventive agent. A prospective, randomized, placebo-controlled clinical trial of combination difluoromethylornithine, a selective inhibitor of polyamine synthesis, and sulindac, a nonsteroidal 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/or multiple adenomas, without evidence of serious toxicities. This proof-of-principle trial indicates that targeting polyamine synthesis and inflammation can be an effective strategy for preventing the occurrence of the advanced and/or multiple adenomas that are most closely associated with the development of colon cancers in humans.
Gerner
Eugene W
EW
The University of Arizona, Arizona Cancer Center, Tucson, Arizona 85724, USA. egerner@azcc.arizona.edu
Meyskens
Frank L
FL
D000236:Adenoma / Q000188:drug therapy; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001120:Arginine / Q000378:metabolism; D002986:Clinical Trials as Topic; D003110:Colonic Neoplasms / Q000235:genetics / Q000517:prevention & control*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D008954:Models, Biological; D011073:Polyamines / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D011073:Polyamines; D001120:Arginine