Increased susceptibility to chemotherapeutic alkylating agents of mice deficient in DNA repair methyltransferase
Increased susceptibility to chemotherapeutic alkylating agents of mice deficient in DNA repair methyltransferase
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DOI：
10.1093/carcin/21.10.1879
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发表时间：
2000-10-01
期刊：
影响因子：
4.7
通讯作者：
Sekiguchi, M
中科院分区：
文献类型：
--
作者：
Shiraishi, A;Sakumi, K;Sekiguchi, M
O-6-甲基鸟嘌呤-DNA甲基转移酶在防止与烷化剂相关的突变和癌症的诱导以及细胞死亡中起着至关重要的作用。用编码甲基转移酶的Mgmt基因缺陷的小鼠评价具有烷基化潜力的治疗剂的细胞死亡诱导和致瘤活性。就存活率而言，Mgmt（-/-）小鼠对达卡巴嗪（一种单功能三氮烯）比野生型小鼠敏感得多。当将达卡巴嗪腹膜内给予6周龄小鼠并计算30天时的存活率时，Mgmt（-/-）和Mgmt（+/+）小鼠的LD 50值分别为20和450 mg/kg体重。（4-氨基-2-甲基-5-嘧啶基）甲基-3-（2-氯乙基）-3-亚硝基脲（ACNU）是一种双功能亚硝基脲。另一方面，暴露于环磷酰胺（一种双功能氮芥）的Mgmt（+/+）和Mgmt（-/-）小鼠的存活率没有差异。似乎达卡巴嗪和ACNU产生O-6-烷基鸟嘌呤作为主要的毒性损伤，而环磷酰胺在DNA中产生不受甲基转移酶作用的其他类型的修饰。Mgmt（-/-）小鼠似乎比Mgmt（+/+）小鼠对达卡巴嗪的肿瘤诱导作用不那么难治。因此，当确定对具有烷基化潜力的药物的敏感性时，O-6-甲基鸟嘌呤-DNA甲基转移酶活性水平是一个重要因素。
O-6-methylguanine-DNA methyltransferase plays vital roles in preventing induction of mutations and cancer as well as cell death related to alkylating agents. Mice defective in the Mgmt gene, encoding the methyltransferase, were used to evaluate cell death-inducing and tumorigenic activities of therapeutic agents which have alkylation potential, Mgmt(-/-) mice were considerably more sensitive to dacarbazine, a monofunctional triazene, than were wild-type mice, in terms of survival. When dacarbazine was administered i.p. to 6-week-old mice and survival at 30 days was enumerated, LD50 values of Mgmt(-/-) and Mgmt(+/+) mice were 20 and 450 mg/kg body wt, respectively, Increased sensitivity of Mgmt(-/-) mice to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), a bifunctional nitrosourea, was also noted. On the other hand, there was no difference in survival of Mgmt(+/+) and Mgmt(-/-) mice exposed to cyclophosphamide, a bifunctional nitrogen mustard. It appears that dacarbazine and ACNU produce O-6-alkylguanine as a major toxic lesion, while cyclophosphamide yields other types of modifications in DNA which are not subjected to the action of the methyltransferase. Mgmt(-/-) mice seem to be less refractory to the tumor-inducing effect of dacarbazine than are Mgmt(+/+) mice, Thus, the level of O-6-methylguanine-DNA methyltransferase activity is an important factor when determining susceptibility to drugs with the potential for alkylation.