三氮的化合物:作用机制和相关的DNA修复系统。

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

三氮的化合物:作用机制和相关的DNA修复系统。

药物杂志》2007年10月;56 (4):275 - 87。Epub 2007年8月9日。

PubMed ID

17897837 (在PubMed

]

文摘

三氮的化合物的临床利益(即达卡巴嗪和temozolomide)是一组具有类似烷基化剂的化学、物理、抗肿瘤和诱变属性。他们的作用机理主要是与O(6)鸟嘌呤的甲基化有关,由methyldiazonium离子,高活性的导数两个化合物。这些药物的细胞毒性和诱变效应是基于DNA的存在O (6) -methylguanine加合物生成基地/基地不匹配与胞嘧啶和胸腺嘧啶。这些加合物导致细胞死亡,或者细胞存活,引起躯体点突变由C: G - - > T: DNA螺旋的过渡。三氮的化合物有良好的动力学特性和有限的毒性。达卡巴嗪需要肝激活而temozolomide自发转化为活性代谢物在生理溶液博士此外,temozolomide完全活跃当管理口服生物利用度(100%)。三氮的化合物的生物效应和细胞抵抗他们的能力取决于至少三个DNA修复系统,(a) (6) -alkylguanine-DNA-alkyltransferase阿,也称为methyl-guanine methyl-transferase(管理);(b)错配修复(MMR)和(c)基地切除修复(BER)。管理是一种小型enzyme-like蛋白质去除小烷基从O(6)位置的DNA加合物通过化学计量和鸟嘌呤auto-inactivating反应。这个反应是由共价转会的烷基烷基化网站的DNA内部管理的半胱氨酸残基的蛋白质。 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.

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药物靶点

药物	目标	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