Deschner E E, Hakissian M, Long F C
Laboratory of Digestive Tract Carcinogenesis, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
J Cancer Res Clin Oncol. 1989;115(4):335-9. doi: 10.1007/BF00400959.
Reciprocal crosses were made between AKR/J, a 1,2-dimethylhydrazine (DMH)-resistant mouse strain, and SWR/J, a sensitive strain. The F1 hybrids were tested with DMH and methylazoxymethanol (MAM), two colon carcinogens. Either DMH (20 mg/kg body weight) or MAM (35 mg/kg body weight), a metabolic derivative of DMH, was injected weekly for 10 weeks. In each group of 35 mice, 10 were injected with tritiated thymidine (25 microCi) 1 week after the sixth injection of DMH and MAM for the evaluation of proliferative characteristics and the number of foci of dysplasia occurring in 325 microns of distal colonic mucosa. At 27 weeks after the first injection of the carcinogen, the colons of remaining mice were opened longitudinally and the number of tumors enumerated. Compared with DMH-treated mice, the number of foci of dysplasia per mouse, the percentage of tumor-bearing mice, the number of tumors per animal, and the number of tumors per tumor-bearing animal induced by MAM were severalfold higher. This would suggest the presence of a gene(s) repressing metabolism of DMH to MAM. Moreover, differences in response to the carcinogens were observed between the sexes. In contrast to males, females treated with both DMH and MAM had significantly greater numbers of tumors per animal, tumors per tumor-bearing mice, and a greater proliferative response with extension of S-phase cells to the upper third and luminal surface of crypts. Among males, those with the XAKR/YSWR heritage appeared more resistant than XSWR/YAKR males, particularly in their response to MAM. A twofold difference in the number of foci of dysplasia per mouse, tumors per animal, and the number of tumors per tumor-bearing animals was seen. Analyses of the response to DMH and MAM by F1 reciprocal hybrids of the AKR and SWR strains have shown a complex inheritance pattern governing susceptibility to DMH. Resistance to the carcinogen is provided by at least two specific repressor genes, one governing metabolism of carcinogen from DMH to MAM, and the other controlled by gender. Genetic factors contributed by the AKR female appear to convey additional resistance to male progeny, suggesting more than one gender-related gene.
对1,2 - 二甲基肼（DMH）抗性小鼠品系AKR/J和敏感品系SWR/J进行了正反交。用两种结肠癌致癌物DMH和甲基偶氮甲醇（MAM）对F1杂种进行测试。每周注射一次DMH（20毫克/千克体重）或MAM（35毫克/千克体重，DMH的一种代谢衍生物），持续10周。在每组35只小鼠中，在第六次注射DMH和MAM后1周，给10只小鼠注射氚标记的胸腺嘧啶核苷（25微居里），以评估增殖特性以及在325微米远侧结肠黏膜中出现的发育异常灶的数量。在首次注射致癌物后27周，将其余小鼠的结肠纵向切开，统计肿瘤数量。与用DMH处理的小鼠相比，MAM诱导的每只小鼠发育异常灶的数量、荷瘤小鼠的百分比、每只动物的肿瘤数量以及每只荷瘤动物的肿瘤数量高出几倍。这表明存在一个抑制DMH代谢为MAM的基因。此外，在性别之间观察到对致癌物反应的差异。与雄性相比，用DMH和MAM处理的雌性每只动物的肿瘤数量、每只荷瘤小鼠的肿瘤数量显著更多，并且随着S期细胞扩展到隐窝的上三分之一和腔表面，增殖反应更强。在雄性中，具有XAKR/YSWR遗传背景的小鼠比X SWR/YAKR雄性更具抗性，尤其是在它们对MAM的反应中。每只小鼠发育异常灶的数量、每只动物的肿瘤数量以及每只荷瘤动物的肿瘤数量存在两倍的差异。对AKR和SWR品系的F1正反交杂种对DMH和MAM的反应分析表明，存在一种复杂的遗传模式控制对DMH的易感性。对致癌物的抗性由至少两个特定的抑制基因提供，一个控制致癌物从DMH到MAM的代谢，另一个受性别控制。AKR雌性贡献的遗传因素似乎赋予雄性后代额外的抗性，表明存在多个与性别相关的基因。
