Oshima M, Oshima H, Tsutsumi M, Nishimura S, Sugimura T, Nagao M, Taketo M M
Banyu Tsukuba Research Institute (Merck), Tsukuba, Japan.
Mol Carcinog. 1996 Jan;15(1):11-7. doi: 10.1002/(SICI)1098-2744(199601)15:1<11::AID-MC3>3.0.CO;2-V.
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.
人类腺瘤性结肠息肉病（APC）基因的损伤不仅会导致家族性腺瘤性息肉病，还会引发整个消化道的许多散发性癌症。利用胚胎干细胞中的同源重组技术，我们最近构建了Apc基因发生截断突变的基因敲除小鼠。这些杂合小鼠会发展出肠道息肉。我们发现，从最早的息肉中分离出的所有微腺瘤都已经失去了野生型等位基因，表明发生了杂合性丢失（LOH）（大岛等人，《美国国家科学院院刊》92:4482 - 4486，1995）。利用这些基因敲除小鼠，我们研究了2 - 氨基 - 1 - 甲基 - 6 - 苯基咪唑并[4,5 - b]吡啶（PhIP）的影响，PhIP是在熟肉和鱼类中发现的最丰富的杂环胺之一。当以400 ppm的剂量给这些小鼠喂食PhIP 8周时，息肉分布转移到更大的尺寸范围，尽管息肉总数没有显著变化。对于其他杂环胺2 - 氨基 - 3 - 甲基咪唑并[4,5 - f]喹啉和2 - 氨基 - 3,8 - 二甲基咪唑并[4,5 - f]喹喔啉，观察到了类似但较弱的效果。另一方面，连续五天以较高剂量（50 mg/kg）腹腔注射2 - 羟基氨基 - 1 - 甲基 - 6 - 苯基咪唑并[4,5 - b]吡啶（N - OH - PhIP）显著增加了息肉数量。这种增加与Apc基因的突变无关；然而，大多数息肉显示全长Apc等位基因丢失（LOH）。这些结果表明，PhIP通过加速微腺瘤的生长速度来影响肠道息肉的发展。高剂量的N - OH - PhIP也有可能增加Apc基因LOH的频率。
