Possible rare involvement of O6-methylguanine formation as a significant mutational factor in mouse urinary bladder carcinogenesis models.
Possible rare involvement of O6-methylguanine formation as a significant mutational factor in mouse urinary bladder carcinogenesis models.
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DOI：
10.1002/(sici)1520-6866(1998)18:3
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发表时间：
1998
期刊：
影响因子：
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通讯作者：
T. Chen;S. Yamamoto;M. Kitano;T. Murai;H. Wanibuchi;S. Matsukuma;Y. Nakatsuru;T. Ishikawa;S. Fukushima
中科院分区：
文献类型：
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作者：
T. Chen;S. Yamamoto;M. Kitano;T. Murai;H. Wanibuchi;S. Matsukuma;Y. Nakatsuru;T. Ishikawa;S. Fukushima
O 6-甲基鸟嘌呤是人类和啮齿类动物致癌过程中的主要致突变前病变之一。O 6-甲基鸟嘌呤-DNA甲基转移酶（MGMT），修复甲基化鸟嘌呤碱基，可能会阻止G：C到A：T的转变，携带这种MGMT基因的转基因小鼠对某些烷化剂的致癌性较不敏感。在这里，我们利用MGMT转基因小鼠来评估膀胱癌发生过程中O 6-甲基鸟嘌呤形成的意义。在实验1中，100和60 ppm N-丁基-N（4-羟丁基）亚硝胺给予转基因和非转基因小鼠的饮用水中，持续20周。膀胱癌的发生率在转基因小鼠和非转基因小鼠之间没有差异。采用聚合酶链反应-单链构象多态性（PCR-SSCP）分析和直接测序法检测p53基因突变谱。转基因和非转基因小鼠的p53突变模式没有差异，突变频率分别为40%和42%。G：C到A：T转换突变特别罕见（14个突变中的1个，7%）。在实验2中，N-甲基-N-亚硝基脲，这可能会导致O 6-甲基鸟嘌呤在受影响的等位基因，每周一次，3次（共5毫克），通过直接滴注到膀胱通过腹部切口。没有检测到显著的肿瘤病变，尽管实验受到治疗的严重毒性的限制。进行p53免疫染色，在转基因和非转基因小鼠中没有差异。这些结果表明，O 6-甲基鸟嘌呤的形成可能不是一个显着的突变因素，在这些小鼠膀胱癌发生模型。
O6-methylguanine is known as one of the major premutagenic lesions in the human and rodent carcinogenesis process. O6-methylguanine-DNA methyltransferase (MGMT), which repairs methylated guanine bases, might prevent the G:C to A:T transition, and transgenic mice carrying this MGMT gene have been reported to be less sensitive to the carcinogenicity of certain alkylating agents. Here we utilized MGMT transgenic mice to assess the significance of O6-methylguanine formation during urinary bladder carcinogenesis. In experiment 1, 100 and 60 ppm N-butyl-N(4-hydroxybutyl)nitrosamine was given for 20 weeks to transgenic and non-transgenic mice in their drinking water. The incidences of urinary bladder carcinomas were not different between transgenic mice and non-transgenic mice. The mutational spectrum of the p53 gene was evaluated by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and direct sequencing. The pattern of p53 mutations of transgenic and non-transgenic mice did not differ, and the frequencies of mutations were 40% and 42%, respectively. G:C to A:T transition mutations were particularly infrequent (1 of 14 mutations, 7%). In experiment 2, N-methyl-N-nitrosourea, which might induce O6-methylguanine in affected alleles, was given once a week, 3 times (total 5 mg) by direct instillation into the urinary bladder through an abdominal incision. No significant neoplastic lesions were detected, although the experiment was limited by severe toxicity of the treatment. p53 immunostaining was done and there was no difference in transgenic and non-transgenic mice. These results suggest that O6-methylguanine formation might not be a significant mutational factor in these mouse urinary bladder carcinogenesis models.