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目的:研究甲基苄肼诱发转基因小鼠MutaTMMouse主要致癌靶器官的cⅡ基因突变谱以及可能的致突变机理,为抗癌药物引发二次肿瘤提供风险-效益评估的依据。方法:甲基苄肼(150 mg.kg-1)连续5 d腹腔注射,14 d后处死动物并取脏器,经λDNA体外包装进行cII筛选,计算突变率并测序分析突变谱。结果:cⅡ突变率在肺、脾、肾分别为128.8×10-6,194.2×10-6和245.0×10-6,比对照组增加约6～9倍;甲基苄肼诱发脾cⅡ突变主要为A:T→T:A碱基颠换。结论:甲基苄肼在体内实验系统产生的腺嘌呤(A)或胸腺嘧啶(T)上的烷化损伤可能是诱发A:T→T:A突变的原因。
OBJECTIVE: To study the mutation of c Ⅱ gene and possible mutagenic mechanism in the major oncogenic target organ of MutaTMMouse induced by procarbazine in transgenic mice, and to provide a basis for risk-benefit evaluation of anticancer drug-induced secondary tumors. METHODS: Methylbenzhydrazine (150 mg · kg -1) was injected intraperitoneally for 5 consecutive days. After 14 days, the animals were sacrificed and organs were removed. The cII was screened by λDNA in vitro. The mutation rate was calculated and the mutation spectrum was analyzed by sequencing. Results: The mutation rate of cⅡ was 128.8 × 10-6, 194.2 × 10-6 and 245.0 × 10-6 respectively in the lung, spleen and kidney, which was about 6 ~ 9 times higher than that of the control group. The mutation of splenic cⅡ induced by procarbazine was mainly A : T → T: A base transversion. CONCLUSIONS: Alzheimer’s disease (alkalosis) on procaine (A) or thymine (T) produced by in vivo experimental systems may be responsible for the A: T → T: A mutation.