Role of polyamines in arginine-dependent colon carcinogenesis in Apc(Min) (/+) mice.
We evaluated the role of polyamines in arginine-dependent intestinal tumorigenesis in Apc(Min) (/+) mice. Arginine is a substrate for ornithine synthesis and thus can influence polyamine production. Supplementing the diet with arginine increased intestinal and colonic polyamine levels and colonic carcinogenesis. Inhibiting polyamine synthesis with D,L-alpha-diflouromethylornithine (DFMO) decreased small intestinal and colonic polyamine pools. In mice provided basal diet, but not when supplemented with arginine, DFMO decreased small intestinal tumor number and burden, and increased intestinal apoptosis. In mice provided supplemental arginine in the diet, DFMO induced late apoptosis and decreased tumorigenesis in the colon. DFMO slightly reduced tumor incidence, number, and size while significantly decreasing tumor burden and grade. These changes in colon tumorigenesis did not occur in mice not provided supplemental arginine. Our study indicates that polyamines play unique roles in intestinal and colonic carcinogenesis in Apc(Min) (/+) mice. Inhibition of polyamine synthesis suppresses the arginine-dependent risk of colon tumorigenesis, resulting in apoptosis induction and decreased tumorigenesis, in this murine model.
Yerushalmi
Hagit F
HF
Gastrointestinal Cancer Program, Arizona Cancer Center, The University of Arizona, Tucson, Arizona 85724, USA.
Besselsen
David G
DG
Ignatenko
Natalia A
NA
Blohm-Mangone
Karen A
KA
Padilla-Torres
Jose L
JL
Stringer
David E
DE
Guillen
Jose M
JM
Holubec
Hana
H
Payne
Claire M
CM
Gerner
Eugene W
EW
D000821:Animal Feed; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000473:pathology; D007408:Intestinal Absorption / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011073:Polyamines / Q000493:pharmacokinetics / Q000494:pharmacology*
D002273:Carcinogens; D011073:Polyamines; D001120:Arginine