新的细胞毒性药物治疗转移性恶性黑素瘤:temozolomide和相关结合鸟嘌呤类似物烷基化剂耐药性废除。
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斯皮罗T,刘L, Gerson年代
新的细胞毒性药物治疗转移性恶性黑素瘤:temozolomide和相关结合鸟嘌呤类似物烷基化剂耐药性废除。
论坛(热那亚)。2000 Jul-Sep; (3): 274 - 85。
- PubMed ID
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11007934 (在PubMed]
- 文摘
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chloroethylating的亚硝基脲(环己亚硝脲、fotemustine cystemustine (BCNU)和甲基化剂temozolomide (TMZ),达卡巴嗪(DTIC)、甲基苄肼)记录活动转移性恶性黑色素瘤与单剂15 - 25%的响应率。Chloroethylating代理形式chloroethyl O6鸟嘌呤的位置加合物,导致N1-guanine N3-cytosine interstrand交联细胞毒性。使甲基化剂攻击DNA在多个站点,尽管大多数的细胞毒性活动是由于在O6甲基加合物的形成鸟嘌呤的位置。这些加合物的存在导致错配修复的徒劳的回收途径导致DNA链断裂和凋亡细胞死亡。一个完整的错配修复系统需要实现他们的细胞毒性效应。DNA加合物的修复DNA修复蛋白O6-alkylguanine alkyltransferase (AGT)损害的细胞毒性作用使甲基化和chloroethylating代理,并调节这些药物的主要阻力路径。在DNA修复,AGT发生不可逆失活。再生AGT活动,新分子的合成是必需的。但变量AGT活动增加在恶性黑素瘤,在转移性更高比原发性肿瘤病变,肿瘤的,高于正常皮肤。AGT的表达活动,在黑色素瘤转移高DTIC化疗治疗前相比,表达。 TMZ alone depletes human AGT in tumour tissue and peripheral blood progenitor cells. As the t1/2 of TMZ via the oral route is short (approximately 1.8 hours), and the anti-tumour activity of the drug is known to be schedule-dependent, twice daily or prolonged administration schedules of TMZ prevent regeneration of AGT, and render tumour cells more sensitive to the drug. O6-benzylguanine (BG) is a potent AGT inactivating agent. BG and its analogues reduce AGT activity, and increase the in vitro and in vivo efficacy of both methylating and chloroethylating agents. In clinical trials, non-toxic doses of BG deplete AGT to undetectable levels. AGT depleting agents in combination with methylating and chloroethylating agents are now in clinical testing, and may result in greater clinical efficacy in metastatic malignant melanoma.