3. 2 拓扑特肯(Topotecan)
它在10 羟喜树碱A 环的9 位加入一个稳定侧链,它有内酯环打开及闭合二种型式,但只有闭合型式才有效,它也抑制拓扑异构酶2 Ⅰ,使DNA 断裂。本药对一系列移值性肿瘤有抑制作用,如对鼠结肠腺癌38 及51、Lewis肺癌及人结肠癌HT29 裸鼠移植瘤有效,对多种抗癌药耐药的肿瘤,用本药仍有效。静脉接种Lewis 肺癌、L1210 白血病小鼠的生命可分别延长94 %及186 %。
Mattexn 等认为本药亚毒性剂量(2mmol/ L) 可加强放射对于对数生长期中国地鼠卵巢细胞(CHO) 或小鼠P 388 白血病细胞在集落形成试验中的杀灭作用。从P388 抗喜树碱株研究中证明这种增敏作用取决于拓扑异构酶Ⅰ的存在。因该抗药细胞缺乏拓扑异构酶Ⅰ,而有拓扑异构酶Ⅱ的上调。这种上调可能通过使DNA 缺损的修复而减弱放射的细胞毒作用。加上拓扑异构Ⅱ抑制剂新生霉素(Novobiocin) 的非毒性剂量处理,则可恢复细胞对放射致死作用的敏感性。单用扑拓特肯3 组NSCLC的59 例中11 例(1816 %) 有效。
4 破坏DNA 结构与功能的药物
4. 1 异环磷酰胺( Ifosfamide , IFO)〔23 ,24〕是环磷酰胺的同分异构体,一个氯乙胺基连结于环上的氮上,而非对称地与另一个氯乙基同时连结于环外的氮上。IFO 可用大剂量(5 g) 以克服对氮芥类的抗药性。它在肝内被氧化成4 羟异环磷酰胺,然后开环,成醛基环磷酰胺,再变为磷酰胺氮芥显效。同时生成的丙烯醛对泌尿道有显著的刺激,同用巯乙磺酸钠(Mesna) 可消除其刺激性,而不影响其疗效。IFO 对NSCLC 疗效亦好,多用联合化疗。IFO + DDP8 组共275 例中90 例(3217 %) 有效,生存期平均619 月。另一方案用VP - 16 + IFO +DDP 的VIP 或ICE 方案,5 组共171 例中52 例(3014 %) 有效, 中数生存期61017 月。
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