【摘要】 氯乙基亚硝脲类烷化剂 (包括CCNU,BCNU,fotemustine等 )是临床上用于抗肿瘤治疗的重要的化疗药物。大多数人类肿瘤由于表达高水平的O6 -烷基鸟嘌呤 -DNA烷基转移酶 (O6 -alkylguanine -DNAalkyltransferase,O6 -AGT)而对烷化剂具有天然抗药性 ,因而严重限制了烷化剂的疗效。O6 -苄基鸟嘌呤 (O6 -benzylguanine,O6 -BG)作为AGT的替代底物 ,不可逆地抑制AGT的活性,而增强烷化剂的化疗效果。然而 ,O6 -BG对AGT转移酶的抑制作用不具有肿瘤细胞特异性 ,在应用O6 -BG增强烷化剂抗肿瘤作用时,甚至会加重烷化剂的剂量限制性毒性作用 -骨髓抑制 ,因此 ,克服骨髓毒性的一条途径便是在应用O6 -BG和烷化剂治疗肿瘤之前 ,应用编码BG -抗药的烷基转移酶基因转导于造血祖细胞 ,保护骨髓。本文论述了O6 -AGT介导肿瘤抗药机制及其在克服肿瘤抗药性和克服骨髓毒性研究中的意义。更多还原

【Abstract】 Background: Chloroethylnitrosoureas including CCNU,BCNU and fotemustine is one of the most important classes of antineoplastic compounds in clinical practice. A number of human tumors are inherently resistant to the cytotoxic effects of alkylating agents due to higher level of O6-alkylguanine-DNA alkyltransferase (O6-AGT) expression. This can limit the therapeutic efficacy of alkylating agents. O6-Benzylguanine (O6-BG) could irreversibly inactivates AGT by acting as an alternative substrate and enhance the therapeutic efficacy. However, O6-BG inhibition of alkyltransferase is not specific for tumor cells. Myelosuppression, which is the dose_limiting side effect of alkylating treatment, would be even more severe with administration of O6-BG and and alkylating agents. Results and Conclusion: One way to overcome this problem would be to transduce hematopoietic cells with a gene encoding a O6-BG-resistant alkyltransferase prior to BG and alkylation treatment.更多还原