Unger C
Klinik fur Tumorbiologie an der Albert-Ludwigs-Universitat Freiburg, Germany.
J Cancer Res Clin Oncol. 1996;122(4):189-98. doi: 10.1007/BF01209645.
General principles for anticancer drug development include traditional drug-screening methods in biological test systems. Today, testing of a drug in a panel of selected human tumor xenografts in mice is assumed to have the best predictive value for clinical efficacy. Chemical modification of well-known antitumor drugs from compound groups such as purine analogs, vinca alkaloids, antifolates and platinum analogs are carried out to increase anticancer activity, to reduce toxic side-effects and to improve pharmacokinetic properties of the drugs. In the last decade the enormous development in molecular techniques has led to the discovery of key proteins that are intimately involved in the regulation of cancer growth control. Cell growth inhibitors could be developed by structure-based design, creating small organic molecules ("peptide mimetics") to target crucial enzymes, oncogenes or oncogene products, tumor-suppressor genes and their products as well as growth factors and their corresponding receptors. Drugs representing new leading structures, like alkylphosphocholines, topoisomerase I inhibitors, taxoids and suramin, have already entered the clinic. Novel therapeutic approaches may provide substantial progress in cancer treatment in the very near future. Examples are the concept of high-dose chemotherapy with hematopoietic stem cell support, the various strategies of gene therapy, the modulation of multi-drug resistance of cancer cells, and strategies to inhibit tumor angiogenesis.
抗癌药物研发的一般原则包括生物测试系统中的传统药物筛选方法。如今,在一组选定的小鼠人肿瘤异种移植模型中对药物进行测试被认为对临床疗效具有最佳预测价值。对嘌呤类似物、长春花生物碱、抗叶酸剂和铂类类似物等化合物组中知名抗肿瘤药物进行化学修饰,以提高抗癌活性、减少毒副作用并改善药物的药代动力学性质。在过去十年中,分子技术的巨大发展导致发现了与癌症生长控制调节密切相关的关键蛋白质。可以通过基于结构的设计开发细胞生长抑制剂,制造小分子有机化合物(“肽模拟物”)来靶向关键酶、癌基因或癌基因产物、肿瘤抑制基因及其产物以及生长因子及其相应受体。代表新主导结构的药物,如烷基磷胆碱、拓扑异构酶I抑制剂、紫杉烷类和苏拉明,已经进入临床。新型治疗方法可能在不久的将来为癌症治疗带来实质性进展。例如,造血干细胞支持下的高剂量化疗概念、基因治疗的各种策略、癌细胞多药耐药性的调节以及抑制肿瘤血管生成的策略。