Effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine on intestinal polyp development in ApcΔ716 knockout mice

Abstract

Damage to the human adenomatous polyposis coli (APC) gene is responsible for not only familial adenomatous polyposis but also many sporadic cancers of the entire digestive tract. Using homologous recombination in embryonic stem cells, we recently constructed gene knockout mice with a truncation mutation in the Apc gene. These heterozygous mice developed intestinal polyps. We found that all microadenomas dissected from the earliest polyps had already lost the wild-type allele, indicating loss of heterozygosity (LOH) (Oshima et al., Proc. Natl. Acad. Sci. USA 92:4482-4486, 1995). Using these knockout mice, we investigated the effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP), one of the most abundant heterocyclic amines found in cooked meat and fish. When PhIP was fed to these mice at 400 ppm for 8 wk, the polyp distribution shifted to a larger size range, although the total polyp number did not change significantly. Similar, but weaker, effects were observed with the other heterocyclic amines 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline. On the other hand, intraperitoneal injections of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhlP) at a higher dose (50 mg/kg) for five consecutive days increased the polyp number significantly. This increment was not associated with mutations in the Apc gene; however, most polyps showed loss of the full-length Apc allele (LOH). These results suggest that PhIP affects intestinal polyp development by accelerating the growth rate of microadenomas. It is also possible that high doses of N-OH-PhIP increase the frequency of Apc gene LOH.

Cyclooxygenase-2 Inhibitors in Tumorigenesis (Part II)

“…This mutant mouse strain provided a useful model system for investigation of various carcinogens and for evaluation of anticancer and chemopreventive agents. In fact, we demonstrated that the heterocyclic amines that are generated in overcooked meat stimulate the growth of the intestinal polyps, whereas feeding the Apc ⌬716 mice docosahexaenoic acid substantially reduces the number of polyps (82,83).…”

Use of Transgenic and Mutant Animal Models in the Study of Heterocyclic Amine-induced Mutagenesis and Carcinogenesis

“…Damage to the human adenomatous polyposis coli (APC) gene is responsible for many cases of sporadic colon cancer and underlies the inherited predisposition known as familial adenomatous polyposis (FAP). Oshima et al (1996) constructed Apc ∆716 knockout mice with a truncation mutation in the Apc gene and found that these mice developed intestinal polyps spontaneously. When PhIP was fed to Apc ∆716 mice at 400 ppm for 8 wk, the total polyp number did not increase significantly but the polyp distribution shifted to a larger size range.…”