Wolff S N, Herzig R H, Fay J W, LeMaistre C F, Brown R A, Frei-Lahr D, Stranjord S, Giannone L, Coccia P, Weick J L
Department of Medicine, Vanderbilt University, Nashville, TN 37232-2535.
Semin Oncol. 1990 Feb;17(1 Suppl 3):2-6.
N,N',N''-triethylenethiophosphoramide (thiotepa) is a polyfunctional alkylating agent similar in structure to nitrogen mustard. Thiotepa (synthesized by American Cyanamid Company, Wayne, NJ) underwent clinical trials in the 1960s that showed that it was active against a wide variety of tumors. At a standard dose level (10 to 30 mg/m2), the dose-limiting toxicity is myelosuppression; other toxicities are infrequent. Therefore, high-dose phase I evaluation was encouraged by these observations. Approximately 217 patients have been treated with single-agent high-dose thiotepa administered intravenously daily over 2 hours for 3 days followed by hematopoietic stem cell rescue to prevent prolonged myelotoxicity. The total doses administered ranged from 135 to 1,575 mg/m2. As anticipated, myelotoxicity was substantial, with 180 mg/m2 being the highest dose not requiring stem cell rescue to ensure hematopoietic recovery. Extramedullary toxicities consisted of stomatitis, dermatitis, hepatoxicity, and central nervous system (CNS) toxicity. CNS toxicity was dose-limiting; other toxicities were problematic, ie, dose-dependent but not truly dose-limiting. The maximal tolerated dose of thiotepa is 900 to 1,125 mg/m2, with the lower dose being the maximal dose for evaluation in combination chemotherapy. In high-dose phase I evaluation, the overall response rate was approximately 50% with responses seen in a wide variety of solid tumors, lymphomas, and pediatric tumors. High-dose thiotepa appears to be an alkylating agent with broad-spectrum antitumor efficacy, which should add to the cytoreductive regimens for both solid and hematopoietic tumors.
氮芥气（噻替派）是一种多官能团烷化剂，其结构与氮芥相似。噻替派（由美国氰胺公司在新泽西州韦恩合成）于20世纪60年代进行了临床试验，结果表明它对多种肿瘤具有活性。在标准剂量水平（10至30mg/m²）下，剂量限制性毒性为骨髓抑制；其他毒性较少见。因此，这些观察结果鼓励进行高剂量I期评估。大约217名患者接受了单药高剂量噻替派治疗，静脉滴注，每日2小时，共3天，随后进行造血干细胞救援以防止长期骨髓毒性。给药的总剂量范围为135至1575mg/m²。正如预期的那样，骨髓毒性很大，180mg/m²是确保造血恢复而无需干细胞救援的最高剂量。髓外毒性包括口腔炎、皮炎、肝毒性和中枢神经系统（CNS）毒性。CNS毒性是剂量限制性的；其他毒性存在问题，即剂量依赖性但并非真正的剂量限制性。噻替派的最大耐受剂量为900至1125mg/m²，较低剂量是联合化疗评估的最大剂量。在高剂量I期评估中，总体缓解率约为50%，在多种实体瘤、淋巴瘤和儿科肿瘤中均可见到缓解。高剂量噻替派似乎是一种具有广谱抗肿瘤疗效的烷化剂，应添加到实体瘤和造血系统肿瘤的细胞减灭方案中。
