抗癌药物发展策略-课件.ppt

进一步研究: (1)阻断端粒酶复合物的组装和转运过程，包括阻断SnRNA在细胞核内的转录，RNA的修饰、加工、转运至细胞质并与蛋白质组装，再返回细胞核的各步骤。(2)阻断端粒DNA与端粒酶活性位点的结合。(3)通过对端粒酶活性细胞内调节机制的调空阻断端粒酶活性，如p53、p21、c-myc、sp1基因等。(4)阻断端粒酶蛋白催化亚基的功能。(5)制备突变端粒酶RNA与内原性RNA竞争端粒酶蛋白。(6)端粒酶蛋白组分抑制剂。(7)端粒酶细胞周期依赖性调节。 存在一些问题：(1)正常人类生殖细胞、表皮细胞、肠黏膜基底干细胞等具有再生能力的细胞中，均可检测到不同水平端粒酶活性的表达，端粒酶活性抑制剂能否对这些细胞产生毒性作用还需考虑。(2)部分肿瘤细胞具有较长端粒(10kb)，随着有丝分裂进行，端粒缩短是个缓慢过程，在此情况下，端粒酶抑制剂是否有效？ (3)人类细胞中可能还存在不依赖端粒酶的端粒替代途径，端粒酶抑制剂能否导致所有肿瘤细胞死亡还有待证实？ (4)人类肿瘤细胞中亦有端粒酶阴性的细胞，可能导致对端粒酶活性的耐药。(5)正常细胞的端粒较多数肿瘤细胞长，且原始干细胞较少进行有丝分裂，其端粒缩短速度低于肿瘤细胞，故端粒酶抑制剂的疗程在正常细胞端粒耗尽前会停止。这样，当抑制端粒酶活性的治疗结束后，正常细胞端粒酶活性是否得到修复还有待研究。 当前对端粒动力学及端粒酶的作用、调控机制认识尚不深入，所以，要将端粒酶抑制剂最终应用于治疗恶性肿瘤尚需更深入的研究和探索。 2009年诺贝尔生理学或医学奖授予美国科学家伊丽莎白·布莱克本(Elizabeth H.Blackburn) 、卡罗尔?格雷德(Carol W.Greider)、和杰克·绍斯塔克(Jack W.Szostak)。 以表彰他们“发现端粒和端粒酶是如何保护染色体的”。 三、靶向药物的现实和展望 Targeted Therapy in the Common Solid Tumors: The Reality Why the Difference? Most solid tumors have complex genetics, not one or two hits but 20+. The more advanced the tumor, the greater the heterogeneity. Molecular heterogeneity. Hitting one narrow target is not likely to be that beneficial. Tumors Progressively Make More Angiogenesis Stimulators Relf et al., Cancer Research, 57:953, 1997 bFGF bFGF VEGF bFGF VEGF PDGF bFGF VEGF PDGFIL-8 How to hit the target If you know the target, and there is only one target you can be very specific. If you don’t really know or it’s a really big target, a larger weapon may be needed. Leveraging your opponents weight, or how targeted therapy can work with other treatments and toss the opponent out of the ring Targeted Therapy: The Future Modern biology has identified a host of new potential targets for cancer therapy Drugs interacting with these targets are available. The benefit of these agents is dependant upon the criticality of the target. More than one target may need to be inhibited. New agents may “tip the balance” when combined with chemotherapy, radiation. Targeted Therapy: The Future (cont’d) The design and careful assessment of new agents in Ph