Aghajanian C, Brown C, O'flaherty C, Fleischauer A, Curtin J, Roemeling R, Spriggs D R
Developmental Chemotherapy Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Gynecol Oncol. 1997 Nov;67(2):127-30. doi: 10.1006/gyno.1997.4841.
Tirapazamine (SR 4233) is a benzotriazine compound exhibiting substantial differential toxicity for hypoxic cells. A large enhancement in tumor cell killing has been demonstrated in preclinical studies when tirapazamine was combined with cisplatin. This phase I study was undertaken to establish a safe dose combination of tirapazamine and cisplatin when administered to patients with recurrent cervical carcinoma.
Tirapazamine was administered as an intravenous infusion over 2 hr, followed 1 hr later by cisplatin intravenously over 1 hr, every 21 days. All patients received prophylactic antiemetics consisting of ondansetron, dexamethasone, and lorazepam. The planned dose escalation levels of tirapazamine were 195, 260, 330, and 390 mg/m2. The cisplatin dose was fixed at 75 mg/m2.
A total of 12 patients were treated with 43 courses of therapy. Patients were heavily pretreated. Eleven of the 12 had prior radiotherapy and 5 of the 12 had prior cisplatin-based chemotherapy. A maximally tolerated dose of 330 mg/m2 was defined for this patient population. The dose-limiting toxicity was nausea and vomiting. All 12 patients were also evaluated for response. Two major responses were seen (17%). In addition, there were three minor responses (25%) and 4 patients achieved disease stabilization (33%). All major and minor responses were seen at the highest dose level tested of 330 mg/m2.
Tirapazamine and cisplatin is an interesting drug combination in the treatment of cervical cancer. Phase II testing is planned.
替拉扎明（SR 4233）是一种对缺氧细胞具有显著差异毒性的苯并三嗪化合物。临床前研究表明，替拉扎明与顺铂联合使用时，肿瘤细胞杀伤作用有大幅增强。本I期研究旨在确定替拉扎明和顺铂联合应用于复发性宫颈癌患者时的安全剂量组合。
替拉扎明通过静脉输注2小时给药，1小时后顺铂静脉输注1小时，每21天重复一次。所有患者均接受由昂丹司琼、地塞米松和劳拉西泮组成的预防性止吐药。替拉扎明计划的剂量递增水平为195、260、330和390mg/m²。顺铂剂量固定为75mg/m²。
共有12例患者接受了43个疗程的治疗。患者均经过大量前期治疗。12例患者中有11例曾接受过放疗，12例中有5例曾接受过基于顺铂的化疗。确定该患者群体的最大耐受剂量为330mg/m²。剂量限制性毒性为恶心和呕吐。对所有12例患者也进行了疗效评估。观察到2例主要缓解（17%）。此外，有3例轻微缓解（25%），4例患者病情稳定（33%）。所有主要和轻微缓解均出现在测试的最高剂量水平330mg/m²。
替拉扎明和顺铂是治疗宫颈癌的一种有前景的药物组合。计划进行II期试验。
