微管稳定剂的研究进展

Advances in the study of microtubule stabilizing agents

微管在细胞的不同进程中起重要的作用,如细胞的新陈代谢、细胞内运输和有丝分裂。以微管为靶点的抗微管药物,是治疗乳腺癌、卵巢癌和肺癌最有效的药物。临床上常用的抗肿瘤药紫杉醇可以促进微管蛋白聚集,抑制肿瘤细胞的快速增殖,但是容易引起多药耐药。新开发的微管稳定剂分为4类:萜类、大环内酯类(如埃坡霉素、伊沙匹隆)、多羟基四烯内酯类和甾类化合物。这些药物与紫杉醇作用机制相似,能对抗由于P糖蛋白外排泵过表达或者微管蛋白突变导致紫杉醇耐药的肿瘤细胞,而且具有良好水溶性。此类药物为治疗癌症提供了新希望。

Microtubules play a key role in cellular metabolism, intracellular transport, and mitosis. Microtubule stabilizing agents is used in the treatment of the solid tumors in breast, ovary, and lung. Paclitaxel is a clinically effective anticancer agent. This agent promotes the polymerization of tubulin into microtubules, and exerts anti-proliferative effects in cancer cell lines. However, tumor ceils can produce muhidrug resistance （MDR） to paclitaxel. Newly developed microtubule stabilizing agents can be divided into three groups： the macrolides, including epothilone, ixabepilone and laulimalide, the polyhydroxylated alkatetraene lactones and the steroids. These agents have potent paclitaxel-like microtubule-stabilizing activity against various aclitaxel-resistant cancer cell lines overexpressing the drug efflux pump P-glycoprotein （P-gp） or harboring tubulin mutations; also these agents exhibit better solubility in aqueous solutions. The microtubule stabilizing agents provide a new hope to treat cancer.