三氮烯类化合物的作用机制及相关的DNA修复系统。

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Marchesi F, Turriziani M, Tortorelli G, Avvisati G, Torino F, De Vecchis L

三氮烯类化合物的作用机制及相关的DNA修复系统。

Pharmacol res 2007 Oct;56(4):275-87。Epub 2007年8月9日。

PubMed ID

17897837 (PubMed视图

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摘要

临床感兴趣的三氮烯化合物(即达卡巴嗪和替莫唑胺)是一组具有相似化学、物理、抗肿瘤和诱变特性的烷基化剂。它们的作用机制主要与O(6)-鸟嘌呤的甲基化有关，甲基重氮离子是这两种化合物的高活性衍生物。这些药物的细胞毒/致突变作用是基于DNA O(6)-甲基鸟嘌呤加合物的存在，该加合物与胞嘧啶和胸腺嘧啶产生碱基/碱基错配。这些加合物导致细胞死亡，或者即使细胞存活，也会引起以C:G—>T: DNA螺旋转变为代表的体细胞点突变。三氮烯类化合物具有优良的药代动力学特性和有限的毒性。达卡巴嗪需要肝脏激活，而替莫唑胺在生理ph的水溶液中自发转化为活性代谢物。此外，替莫唑胺口服时完全有效(100%生物利用度)。三氮烯化合物的生物学效应和细胞对它们的抗性取决于至少三种DNA修复系统，(a) O(6)-烷基鸟嘌呤-DNA烷基转移酶，也称为甲基鸟嘌呤甲基转移酶(MGMT);(b)错配修复(MMR)和(c)基切除修复(BER)。MGMT是一种小的类酶蛋白，通过化学计量学和自动灭活反应，从DNA鸟嘌呤的O(6)位置去除小的烷基加合物。该反应由烷基基从DNA的烷基化位点共价转移到MGMT蛋白的内部半胱氨酸残基。 High levels of MGMT are responsible for normal and tumour cell resistance to triazenes. Therefore, pre-treatment with MGMT inhibitors - i.e. O(6)-benzylguanine or O(6)-(4-bromotenyl)guanine (Lomeguatrib) - is followed by a great increase in the activity of triazenes against target cells expressing high MGMT levels. MMR is represented by a protein complex dedicated to the repair of biosynthetic errors generated during DNA replication. The MMR system recognizes base mismatches and insertion-deletion loops, cuts the nucleotide sequence containing the lesion, and restores the correct base sequence. Therefore, not only MGMT but also MMR is involved in target cell susceptibility to triazenes. However, the system does not suppress, but instead promotes the cytotoxic effects of triazenes. In fact, MMR is not able to repair the incorrect base pairing determined by treatment with triazenes and, according to a predominant hypothesis, it causes reiterated "futile" attempts of damage repair leading to the activation of cell cycle arrest and apoptosis. BER removes lesions due to cellular metabolism, or to physical or chemical agents. BER is able to repair N(7)-methylguanine and N(3)-methyladenine determined by treatment with triazenes. Therefore, triazene compounds can also kill tumour cells by a N(3)-methyladenine-mediated mechanism if BER activity is inhibited by chemical agents (i.e. PARP inhibitors). In conclusion, in selected cases, triazenes can represent a therapeutic alternative to treatment of neoplastic diseases including haematological malignancies. Moreover, the susceptibility of neoplastic cells to these compounds can be substantially increased through pharmacological modulation of the expression level and functional activity of DNA repair enzymes.

引用本文的药物库数据

药物靶点

药物	目标	种类	生物	药理作用	行动
Temozolomide	DNA	核苷酸	人类	是的	交联/烷基化	细节