DNA repair methyltransferase (Mgmt) knockout mice are sensitive to the lethal effects of chemotherapeutic alkylating agents
DNA repair methyltransferase (Mgmt) knockout mice are sensitive to the lethal effects of chemotherapeutic alkylating agents
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DOI：
10.1093/mutage/14.3.339
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发表时间：
1999-05-01
期刊：
影响因子：
2.7
通讯作者：
Samson, LD
中科院分区：
文献类型：
--
作者：
Glassner, BJ;Weeda, G;Samson, LD
我们用同源重组的方法去除编码Mgmt活性部位半胱氨酸的区域，产生了Mgmt基因编码的o -6-甲基鸟嘌呤DNA甲基转移酶活性不足的小鼠，Mgmt基因缺失小鼠的组织显示出非常低的o -6-甲基鸟嘌呤DNA甲基转移酶活性，这表明Mgmt基因构成了主要的（如果不是唯一的）o -6-甲基鸟嘌呤DNA甲基转移酶。Mgmt -/-小鼠的原代小鼠胚胎成纤维细胞和骨髓细胞对化学化剂1,3-双（2-氯乙基）-1-亚硝基脲、链脲佐菌素和替莫唑胺的毒性作用明显比Mgmt野生型小鼠敏感。正如预期的那样，Mgmt缺陷的成纤维细胞和骨髓细胞对紫外光或交联剂丝裂霉素c不敏感。此外，Mgmt- /-小鼠的50%致死剂量比Mgmt +/+小鼠的1,3-双（2-氯乙基）-1-亚硝基脲、n -甲基-n -亚硝基脲和链脲佐菌素低2- 10倍；在丝裂霉素C中观察到类似的50%致死剂量，野生型和Mgmt -/-小鼠在药物治疗后的尸检显示组织学证据表明造血组织明显消融，但Mgmt -/-小鼠的这种消融发生在低剂量的小鼠中。这些结果表明，o -6-甲基鸟嘌呤DNA甲基转移酶在保护细胞和动物免受用于癌症化疗的烷基化剂的毒性作用方面至关重要。
We have generated mice deficient in O-6-methylguanine DNA methyltransferase activity encoded by the murine Mgmt gene using homologous recombination to delete the region encoding the Mgmt active site cysteine, Tissues from Mgmt null mice displayed very low O-6-methylguanine DNA methyltransferase activity, suggesting that Mgmt constitutes the major, if not the only, O-6-methylguanine DNA methyltransferase. Primary mouse embryo fibroblasts and bone marrow cells from Mgmt -/- mice were significantly more sensitive to the toxic effects of the chemotherapeutic alkylating agents 1,3-bis (2-chloroethyl)-1-nitrosourea, streptozotocin and temozolomide than those from Mgmt wild-type mice. As expected, Mgmt-deficient fibroblasts and bone marrow cells were not sensitive to UV light or to the crosslinking agent mitomycin C. In addition, the 50% lethal doses for Mgmt -/- mice were 2- to 10-fold lower than those for Mgmt +/+ mice for 1,3-bis(2-chloroethyl)-1-nitrosourea, N-methyl-N-nitrosourea and streptozotocin; similar 50% lethal doses were observed for mitomycin C, Necropsies of both wild-type and Mgmt -/- mice following drug treatment revealed histological evidence of significant ablation of hematopoietic tissues, but such ablation occurred at much lower doses for the Mgmt -/- mice. These results demonstrate the critical importance of O-6-methylguanine DNA methyltransferase in protecting cells and animals against the toxic effects of alkylating agents used for cancer chemotherapy.