Temozolomide:行动的机制,修复和阻力。

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张J,史蒂文斯MF,布拉德肖道明

Temozolomide:行动的机制,修复和阻力。

咕咕叫摩尔杂志。2012年1月,5(1):102 - 14所示。doi: 10.2174 / 1874467211205010102。

PubMed ID
22122467 (在PubMed
]
文摘

多形性胶质母细胞瘤是最常见的成人中枢神经系统的主要肿瘤。治疗包括手术、放疗和辅助temozolomide (TMZ)化疗。TMZ的烷化剂前体药物,提供一个甲基嘌呤碱基的DNA (O6-guanine;N7-guanine和N3-adenine)。主细胞毒性损伤,O6-methylguanine (O6-MeG)可以被methylguanine甲基转移酶(管理;直接修复)在肿瘤表达这种蛋白质,或容忍不匹配repair-deficient (MMR)肿瘤。因此管理或MMR缺乏对TMZ产生了耐药性。固有的和获得性耐药TMZ现在成功治疗的主要障碍。策略设计了阻止阻力,提高应对TMZ,包括抑制DNA修复机制有助于TMZ阻力,正在临床评价。烷化剂化疗前消耗的管理防止O6-MeG修理; thus, MGMT pseudosubstrates O6-benzylguanine and lomeguatrib are able to sensitise tumours to TMZ. Disruption of base excision repair (BER) results in persistence of potentially lethal N7- and N3- purine lesions contributing significantly to TMZ cytoxicity particularly when O6-MeG adducts are repaired or tolerated. Several small molecule inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1), a critical BER protein are yielding promising results clinically, both in combination with TMZ and as single agent chemotherapy in patients whose tumours possess homologous recombination DNA repair defects. Another validated, but as yet preclinical protein target, mandatory to BER is abasic (AP) endonuclease-1 (APE-1); in preclinical tests, APE-1 inhibition potentiates TMZ activity. An alternative strategy is synthesis of a molecule, evoking an irrepairable cytotoxic O6-G lesion. Preliminary efforts to achieve this goal are described.

DrugBank数据引用了这篇文章

药物
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
药物反应
反应
Temozolomide
DB00853
    Temozolomide羧酸代谢物(TMA)
    DBMET03266
    		细节
    Temozolomide
    DB00853
      (5)- 3-methyltriazen-1-yl imidazole-4-carboxamide (MTIC)
      DBMET03267
      		细节