Temozolomide and treatment of malignant glioma.
Temozolomide and treatment of malignant glioma.
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发表时间：
2000-07
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通讯作者：
H. Friedman;T. Kerby;H. Calvert
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作者：
H. Friedman;T. Kerby;H. Calvert
恶性胶质瘤(多形性胶质母细胞瘤和间变性星形细胞瘤)比其他类型的原发中枢神经系统肿瘤更常见，总发病率为5-8/10万人。即使使用手术、放疗和化疗进行积极治疗，中位生存期也不到一年。替莫唑胺是一种新药，在治疗恶性胶质瘤和其他难以治疗的肿瘤方面显示出了希望。替莫唑胺，一种P.O.咪唑四嗪是第二代烷基化试剂，是一类进入脑脊液且不需要肝脏代谢即可激活的新型化疗药物中的主导化合物。在体外，替莫唑胺对高度耐药的恶性肿瘤，包括高级别胶质瘤，表现出依赖于时间表的抗肿瘤活性。在临床研究中，替莫唑胺在大约100%P.O.生物利用度，快速可逆的非累积最小骨髓抑制，以及对儿童和成人各种实体肿瘤的活性。临床前研究评估了替莫唑胺与其他烷化剂和DNA修复蛋白O6-烷基鸟嘌呤烷基转移酶抑制剂联合使用，以克服恶性胶质瘤和恶性转移性黑色素瘤对化疗的耐药性。替莫唑胺最近在美国被批准用于治疗难治性间变性星形细胞瘤的成人患者，在欧盟被批准用于治疗在标准治疗后出现进展或复发的多形性胶质母细胞瘤。可预测的生物利用度和最小的毒性使替莫唑胺成为评估不同肿瘤类型联合治疗潜力的广泛临床试验的候选对象。现就替莫唑胺的作用机制和临床试验结果进行综述。
Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) occur more frequently than other types of primary central nervous system tumors, having a combined incidence of 5-8/100,000 population. Even with aggressive treatment using surgery, radiation, and chemotherapy, median reported survival is less than 1 year. Temozolomide, a new drug, has shown promise in treating malignant gliomas and other difficult-to-treat tumors. Temozolomide, a p.o. imidazotetrazine second-generation alkylating agent, is the leading compound in a new class of chemotherapeutic agents that enter the cerebrospinal fluid and do not require hepatic metabolism for activation. In vitro, temozolomide has demonstrated schedule-dependent antitumor activity against highly resistant malignancies, including high-grade glioma. In clinical studies, temozolomide consistently demonstrates reproducible linear pharmacokinetics with approximately 100% p.o. bioavailability, noncumulative minimal myelosuppression that is rapidly reversible, and activity against a variety of solid tumors in both children and adults. Preclinical studies have evaluated the combination of temozolomide with other alkylating agents and inhibitors of the DNA repair protein O6-alkylguanine alkyltransferase to overcome resistance to chemotherapy in malignant glioma and malignant metastatic melanoma. Temozolomide has recently been approved in the United States for the treatment of adult patients with refractory anaplastic astrocytoma and, in the European Union, for treatment of glioblastoma multiforme showing progression or recurrence after standard therapy. Predictable bioavailability and minimal toxicity make temozolomide a candidate for a wide range of clinical testing to evaluate the potential of combination treatments in different tumor types. An overview of the mechanism of action of temozolomide and a summary of results from clinical trials in malignant glioma are presented here.