Impact of dietary amino acids and polyamines on intestinal carcinogenesis and chemoprevention in mouse models.
Colon cancer in humans is influenced by both genetic and dietary risk factors. The majority of colon cancers have somatic mutations in the APC (adenomatous polyposis coli) tumour-suppressor gene. Dietary arginine enhances the risk of APC-dependent colon carcinogenesis in mouse models by a mechanism involving NOS2 (nitric oxide synthase 2), as elimination of NOS2 alleles suppresses this phenotype. DFMO (difluoromethylornithine), a specific inhibitor of polyamine synthesis, also inhibits dietary arginine-induced colon carcinogenesis in C57BL/6J-Apc(Min)/J mice. The primary consequence of dietary arginine is to increase the adenoma grade in these mice. Either loss of NOS2 alleles or inhibition of polyamine synthesis suppresses the arginine-induced increase in adenoma grade. In addition to promoting intestinal carcinogenesis, polyamines can also reduce the efficacy of certain intestinal cancer chemopreventive agents. The NSAID (non-steroidal anti-inflammatory drug) sulindac is a potent inhibitor of intestinal carcinogenesis in the C57BL/6J-Apc(Min)/J mouse model and is used to treat humans with FAP (familial adenomatous polyposis). Dietary putrescine reduces the ability of sulindac to suppress intestinal tumorigenesis in the mouse model. These data suggest that reducing polyamine metabolism and dietary polyamine levels may enhance strategies for colon cancer chemoprevention.
Gerner
E W
EW
Department of Cell Biology and Anatomy, The University of Arizona, Arizona Cancer Center, Tucson, AZ 85724, USA. egerner@azcc.arizona.edu
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000517:prevention & control*; D004032:Diet; D004195:Disease Models, Animal; D000518:Eflornithine / Q000627:therapeutic use; D006801:Humans; D007414:Intestinal Neoplasms / Q000517:prevention & control*; D051379:Mice; D011073:Polyamines / Q000494:pharmacology*
D000596:Amino Acids; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D011073:Polyamines; D000518:Eflornithine