Kavallaris M, Verrills N M, Hill B T
Children's Cancer Institute for Medical Research, Randwick, NSW, Australia.
Drug Resist Updat. 2001 Dec;4(6):392-401. doi: 10.1054/drup.2002.0230.
Antimitotic agents that target tubulin, including the taxanes and vinca alkaloids, are important components of current anticancer therapy. Whilst these antimitotic drugs are highly effective in the treatment of a number of cancers, both acquired and intrinsic resistance to these agents is a major clinical problem. Furthermore, the systemic toxicity, and in some cases lack of oral availability, make these agents less than ideal. Recently much effort has been directed on the isolation and synthesis of new antimitotic drugs that target the tubulin/microtubule system and display efficacy against drug-refractory carcinomas. Newly described compounds include structurally diverse natural products, such as dolastatin, epothilones and discodermolide, derivatives and structural analogues of traditional antimitotics, and novel synthetic molecules. Additionally, new developments in drug targeting are improving efficacy and therapeutic indices of traditional agents. A number of promising 'new generation' antimitotics are now undergoing clinical testing. These new agents are reviewed here in terms of their mechanism(s) of action on microtubules, effectiveness against drug-resistant tumour cells and clinical potential.
靶向微管蛋白的抗有丝分裂药物，包括紫杉烷类和长春花生物碱，是当前抗癌治疗的重要组成部分。虽然这些抗有丝分裂药物在治疗多种癌症方面非常有效，但对这些药物的获得性耐药和固有耐药都是一个主要的临床问题。此外，全身毒性以及在某些情况下缺乏口服可用性，使得这些药物并不理想。最近，人们致力于分离和合成新的抗有丝分裂药物，这些药物靶向微管蛋白/微管系统，并对难治性癌显示出疗效。新描述的化合物包括结构多样的天然产物，如多拉司他汀、埃坡霉素和盘状软骨素，传统抗有丝分裂药物的衍生物和结构类似物，以及新型合成分子。此外，药物靶向的新进展正在提高传统药物的疗效和治疗指数。一些有前景的“新一代”抗有丝分裂药物正在进行临床试验。本文根据这些新药对微管的作用机制、对耐药肿瘤细胞的有效性和临床潜力进行综述。
