Topotecan -我一个新颖的拓扑异构酶抑制剂:药理学和临床经验。
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Kollmannsberger C, mro K,雅克布,Kanz L, Bokemeyer C
Topotecan -我一个新颖的拓扑异构酶抑制剂:药理学和临床经验。
肿瘤。1999;56 (1):1 - 12。
- PubMed ID
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9885371 (在PubMed]
- 文摘
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Topotecan,喜树碱的水溶性模拟,是一个新细胞毒性剂可用作为抑制剂的拓扑异构酶I, DNA复制所必需的酶。Topotecan来自喜树碱是半合成产品,它被发现在一个国家癌症研究所细胞毒性药物筛选项目近30年前。它的作用与DNA形成一个稳定的共价复杂/拓扑异构酶聚合,所谓的“可分裂的复杂”。这个过程会导致DNA链的断裂导致细胞凋亡和细胞死亡。Topotecan具有血清半衰期约3 h,大量的分布与高组织吸收和低蛋白结合。化学结构是基于一个内酯环。Topotecan发生可逆的水解从其生物活性内酯开环不活跃的羧酸盐形式形式。它也能够穿透完整的血脑屏障。因为大多数的代理是由肾脏排泄,肾功能受损时剂量的调整是必要的。相比之下,药代动力学行为是有限的患者肝脏功能不变。 The principal toxicity of topotecan when administered at standard doses is neutropenia, but thrombocytopenia and anemia occur as well, while the nonhematological toxicities are usually mild. Alopecia is frequently observed and some patients may suffer from pronounced fatigue. Most clinical data available are based on the following schedule: 1.5 mg/m2 topotecan given as a 30-min infusion, days 1-5. There are currently only minimal data available regarding a dose-antitumor activity relationship. Other topotecan administration schedules are currently being investigated. Preclinical data suggest that continuous-infusion schedules may be a better application form in terms of both, toxicity and antitumor activity. However, clinical trials could not confirm these results to date. Results of phase II studies suggest considerable antitumor activity of single agent topotecan in small cell lung cancer and ovarian cancer patients. A randomized phase III trial of topotecan versus paclitaxel in ovarian cancer patients pretreated with cisplatin/cyclophosphamide has demonstrated that topotecan is as effective as paclitaxel in the second-line treatment of these patients. Activity of topotecan was also observed in non-small-cell lung cancer, refractory leukemias/myelodysplastic syndromes and in childhood sarcomas. Due to its unique mechanism of action and lack of cross-resistance, cisplatin, etoposide, cytarabine and paclitaxel are potential interacting partners for combination chemotherapy regimens. However, the best combination regimen as well as the optimal combination schedule have yet to be conclusively determined. The potential of topotecan in a variety of solid tumors, as well as its use in combination regimens for ovarian and small cell lung cancer is currently being investigated.