Geney R, Chen J, Ojima I
Institute of Chemical Biology & Drug Discovery and Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794-3400, USA.
Med Chem. 2005 Mar;1(2):125-39. doi: 10.2174/1573406053175292.
Recent advances in the design and preclinical evaluations of promising new generation taxane anticancer agents are reviewed in this article. Paclitaxel and docetaxel are two of the most important anticancer drugs today. However, recent reports have shown that treatment with these drugs often encounters undesirable side effects as well as drug resistance. Therefore, it is important to develop new taxane anticancer agents with fewer side effects, superior pharmacological properties, and improved activity against drug-resistant human cancers. Structure-activity relationship (SAR) studies led to the discovery of a series of highly active second-generation taxanes. One of them, "Ortataxel" (SB-T-101131, IDN5109, BAY59-8862), exhibits excellent activity against a variety of drug-sensitive and drug-resistant cancer cell lines, as well as human tumor xenografts in mice. It is orally active and is currently in phase II clinical trials. Photoaffinity labeling of microtubules and P-glycoprotein using photoreactive radiolabeled taxoids has disclosed the drug-binding domain of tubulin as well as Pgp. Together with information on microtubule-bound fluorine-labeled taxoids obtained by solid-state NMR studies, the bioactive conformation of paclitaxel and taxoids appears to emerge. Novel taxane-monoclonal antibody (mAb) immunoconjugates, have shown highly promising results for the tumor-specific delivery and release of an extremely cytotoxic, second-generation taxane. Also, another novel series of second generation taxanes conjugated with n-3 polyunsaturated fatty acids, e.g. decosahexaenoic acid (DHA), has exhibited impressive antitumor activity with minimum general toxicity against the highly drug-resistant DLD-1 human colon cancer xenografts in SCID mice.
本文综述了新一代有前景的紫杉烷类抗癌药物在设计和临床前评估方面的最新进展。紫杉醇和多西他赛是当今最重要的两种抗癌药物。然而，最近的报道表明，使用这些药物进行治疗时常常会出现不良副作用以及耐药性。因此，开发副作用更少、药理特性更优且对耐药性人类癌症活性更高的新型紫杉烷类抗癌药物具有重要意义。构效关系（SAR）研究促成了一系列高活性第二代紫杉烷类药物的发现。其中之一，“奥他赛”（SB-T-101131、IDN5109、BAY59-8862），对多种药物敏感和耐药癌细胞系以及小鼠体内的人肿瘤异种移植模型均表现出优异的活性。它具有口服活性，目前正处于II期临床试验阶段。使用光反应性放射性标记紫杉烷类药物对微管和P-糖蛋白进行光亲和标记，揭示了微管蛋白以及Pgp的药物结合域。结合通过固态核磁共振研究获得的关于微管结合氟标记紫杉烷类药物的信息，紫杉醇和紫杉烷类药物的生物活性构象似乎逐渐明晰。新型紫杉烷-单克隆抗体（mAb）免疫缀合物在肿瘤特异性递送和释放极具细胞毒性的第二代紫杉烷方面显示出非常有前景的结果。此外，另一系列与n-3多不饱和脂肪酸（如二十二碳六烯酸（DHA））缀合的新型第二代紫杉烷，对SCID小鼠体内高度耐药的DLD-1人结肠癌异种移植模型表现出令人印象深刻的抗肿瘤活性，且总体毒性最小。
