Arioka H, Saijo N
Dept. of Medical Oncology, National Cancer Center Central Hospital, Tokyo, Japan.
Gan To Kagaku Ryoho. 1994 Apr;21(5):583-90.
Microtubules, which are composed of polymerized tubulin dimers, play an important role in various cell functions. For example, they maintain cell shape, form mitotic spindles in M phase of cell cycle, and carry an axonal transport in nerve cells. Microtubules have also been an important target of cancer chemotherapy. Vinca alkaloids depolymerize microtubules, the mechanisms of which action have extensively been investigated recently. Clinical trials of vinorelbine (navelbine), a new semisynthetic vinca alkaloid, are ongoing in Japan. One of advantages of the drug is reduced risk of neurotoxicity. Estramustine may act on microtubule-associated proteins (MAPs) as well as tubulin. It shows additive or synergistic cytotoxicity preclinically when used in combination with vinblastine. This combination was active against hormone-refractory prostate cancer. Another novel drug rhizoxin, which has a similar mechanism of action to that of vinca alkaloids, is also a promising cytotoxic agent and is examined clinically in Europe. Taxanes, which include paclitaxel (Taxol) and taxotere, are interesting drugs because they promote polymerization of tubulin and stabilize microtubules. They show promising antitumor activity against breast, ovarian and lung cancers. Phase I and II trials are ongoing in Japan. Paclitaxel may also potentiate cytotoxicity of radiation. There are several mechanisms of resistance to microtubule-acting drugs. One is multidrug resistance mediated by P-glycoprotein. Other mechanisms include mutation of tubulin.
微管由聚合的微管蛋白二聚体组成，在各种细胞功能中发挥重要作用。例如，它们维持细胞形状，在细胞周期的M期形成有丝分裂纺锤体，并在神经细胞中进行轴突运输。微管也是癌症化疗的重要靶点。长春花生物碱使微管解聚，其作用机制最近已得到广泛研究。一种新的半合成长春花生物碱长春瑞滨（诺维本）正在日本进行临床试验。该药物的优点之一是神经毒性风险降低。雌莫司汀可能作用于微管相关蛋白（MAPs）以及微管蛋白。临床前研究表明，当与长春碱联合使用时，它具有相加或协同的细胞毒性。这种联合用药对激素难治性前列腺癌有效。另一种新型药物根霉素，其作用机制与长春花生物碱相似，也是一种有前景的细胞毒性药物，正在欧洲进行临床试验。紫杉烷类药物，包括紫杉醇（泰素）和多西他赛，是一类有趣的药物，因为它们促进微管蛋白的聚合并稳定微管。它们对乳腺癌、卵巢癌和肺癌显示出有前景的抗肿瘤活性。日本正在进行I期和II期试验。紫杉醇还可能增强放疗的细胞毒性。对微管作用药物存在多种耐药机制。一种是由P-糖蛋白介导的多药耐药。其他机制包括微管蛋白的突变。
