Geney Raphaël, Ungureanu loana Maria, Li Dansu, Ojima Iwao
Department of Chemistry, State University of New York at Stony Brook, 11794-3400, USA.
Clin Chem Lab Med. 2002 Sep;40(9):918-25. doi: 10.1515/CCLM.2002.161.
Paclitaxel (Taxol) and docetaxel (Taxotère) are currently two of the most important anticancer drugs in cancer chemotherapy. However, clinical treatment with these taxane agents often encounters undesirable side effects and multidrug resistance (MDR) caused by overexpression of P-glycoprotein (Pgp). Photoaffinity labeling of Pgp using photoreactive radiolabeled paclitaxel analogs along with molecular modeling has revealed a unique binding region for paclitaxel on the C-terminal half of Pgp. Highly efficient taxane-based MDR reversal agents (TRAs) have been developed. Extensive structure-activity relationship (SAR) studies have led to the development of new generation taxanes that possess 2-3 orders of magnitude higher potencies against human cancer cell lines expressing the MDR phenotype. One of these taxanes, SB-T-1 10131 (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. This taxane is orally active with excellent bioavailability, and is currently undergoing phase II human clinical trials. Novel taxane-antibody immunoconjugates have shown very promising results for tumor-specific delivery and release of an extremely cytotoxic taxane, wherein epidermal growth factor receptor is used as the specific antigen on the tumor surface of human squamous cancer xenograft in SCID mice.
紫杉醇（泰素）和多西他赛（泰索帝）是目前癌症化疗中最重要的两种抗癌药物。然而，使用这些紫杉烷类药物进行临床治疗时，常常会遇到不良副作用以及由P-糖蛋白（Pgp）过度表达引起的多药耐药性（MDR）。利用光反应性放射性标记的紫杉醇类似物对Pgp进行光亲和标记并结合分子建模，揭示了紫杉醇在Pgp C端的独特结合区域。已经开发出了高效的基于紫杉烷的多药耐药逆转剂（TRA）。广泛的构效关系（SAR）研究促使新一代紫杉烷的研发，这些新一代紫杉烷对表达MDR表型的人类癌细胞系具有高2 - 3个数量级的效力。其中一种紫杉烷，SB-T-1 10131（IDN5109，BAY59-8862），对多种药物敏感和耐药癌细胞系以及小鼠体内人肿瘤异种移植模型均表现出优异的活性。这种紫杉烷具有口服活性且生物利用度极佳，目前正在进行II期人体临床试验。新型紫杉烷 - 抗体免疫缀合物在肿瘤特异性递送和释放极具细胞毒性的紫杉烷方面已显示出非常有前景的结果，其中表皮生长因子受体被用作SCID小鼠中人鳞状癌异种移植瘤肿瘤表面的特异性抗原。
