title: Efficient induction of rat large intestinal tumors with a new spectrum of mutations by intermittent administration of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in combination with a high fat diet.
abstract: In the present study we have established novel intermittent protocols featuring a high fat (HF) diet for efficient induction of large intestinal tumors with a relatively small amount of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). In protocol 1, F344 male rats were first fed a diet containing 400 p.p.m. PhIP for 2 weeks, followed by continuous administration of a HF diet without PhIP for 108 weeks. In protocol 2, 2 week PhIP treatments were repeated three times with 4 week intervals on the HF diet alone, followed by continuous feeding of the HF diet for 42 weeks. At termination of the experiments, 16 (3 of 19) and 45% (9 of 20) of the rats had developed a total of three and 13 large intestinal tumors with protocols 1 and 2, respectively. The tumor incidence in protocol 2 was comparable with that observed with continuous feeding of 400 p.p.m. PhIP for 52 weeks, after exposure to only approximately 10% of the amount of carcinogen. Five of nine (55%) tumors harbored mutations in either the beta-catenin or Apc gene, while all demonstrated accumulation of beta-catenin protein in the cytoplasm and nucleus. This suggests that other unknown genetic alterations in the Wnt-Apc-beta-catenin signaling pathway could have been involved in the development of tumors. By further modifying this intermittent protocol with HF diet, one could expect more efficient induction of lesions with much smaller amounts of PhIP in a shorter period. In addition, this model could provide a means to elucidate genetic alterations in large intestinal tumors induced by relatively low levels of carcinogenic insult, mimicking the cases of human colon carcinogenesis induced by exposure to environmental carcinogens.
authors.affiliation: Biochemistry Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Tsuneyuki
authors.initials: T
authors.lastname: Ubagai
authors.forename: Masako
authors.initials: M
authors.lastname: Ochiai
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kawamori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Imai
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugimura
authors.forename: Minako
authors.initials: M
authors.lastname: Nagao
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D004041:Dietary Fats / Q000494:pharmacology*; D004357:Drug Synergism; D007093:Imidazoles / Q000494:pharmacology*; D007414:Intestinal Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D007420:Intestine, Large / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D051381:Rats; D011916:Rats, Inbred F344; D015534:Trans-Activators; D051176:beta Catenin
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D004041:Dietary Fats; D007093:Imidazoles; D015534:Trans-Activators; D051176:beta Catenin; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine