抗癌药甲基苄肼诱发转基因小鼠(Muta^(TM) Mouse)cⅡ基因A:T→T:A碱基颠换

Procarbazine induces A:T→T:A transversion in the cII gene in Muta^(TM) Mouse

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 reveal the molecular nature of the mutations,we analyzed the sequence of cⅡ mutations induced by procarbazine in the drug＇s target organs for carcinogenesis of MutaTMMouse in the present report.Methods： Procarbazine was intraperitoneally injected into mice at a daily dose of 150 mg·kg-1 for 5 consecutive days.The mice were killed 14 days after the final treatment,and the organs were immediately extirpated for the extraction of DNA.After DNA packaging,cⅡ mutant frequency（MF） and sequencing of mutants were analyzed.Results： The cⅡ mutant frequency in lung,spleen,and kidney,which increased almost 6～9 times,was 128.8×10-6,194.2×10-6 and 245.0×10-6.The majority of procarbazine-induced mutations were A：T to T：A transversions.Conclusion： Procarbazine probably causing adenine or thymine injuries to induce A：T to T：A mutations besides mutagenic O6-methylguanine.