Davila E, Klein L, Vogel C L, Johnson R, Ostroy F, Browning S, Gorowski E, Furner R L, Presant C A
J Clin Oncol. 1985 Jan;3(1):121-7. doi: 10.1200/JCO.1985.3.1.121.
Misonidazole, a hypoxic cell sensitizer, enhances the antitumor effects of cyclophosphamide in preclinical studies. Several studies also showed increased cytotoxicity for normal tissues. We undertook a phase I study of this combination. The regimen consisted of oral administration of misonidazole at one of two dose levels, 1 g/m2 and 2 g/m2, followed by an intravenous (IV) injection of cyclophosphamide four hours later. The cycle was repeated every twenty-one days. The dose of misonidazole remained constant for each regimen, but the dose of cyclophosphamide ranged from 0.4 g/m2 to 1.3 g/m2. Thirty-eight trials in 35 patients with advanced solid tumors were considered evaluable. Dose-limiting toxicity was granulocytopenia at 1 g/m2 of cyclophosphamide without significant thrombocytopenia or anemia. Peripheral neuropathy was negligible. Two patients received cumulative doses of 8 and 16 g/m2 of misonidazole without neurotoxicity. One patient developed hemorrhagic cystitis. Nausea and vomiting was mild to moderate. Possible evidence of tumor stabilization was seen in three patients, and one patient had a mixed response. The mean serum half-life for misonidazole was 11.3 hours (range, 8.4 to 20.0) and for cyclophosphamide 8.3 hours (range, 3.2 to 15.5), both within the previously reported ranges. In conclusion, it appears that this combination is well tolerated and that misonidazole does not significantly potentiate myelotoxicity caused by cyclophosphamide or alter its pharmacokinetics. The recommended starting doses for misonidazole and cyclophosphamide in phase II trials using this schedule of administration should be 2 g/m2 and 1 g/m2, respectively, with escalation for cyclophosphamide to individual tolerance.
米索硝唑是一种低氧细胞增敏剂，在临床前研究中可增强环磷酰胺的抗肿瘤作用。多项研究还表明其对正常组织的细胞毒性增加。我们开展了该联合用药的I期研究。治疗方案为口服米索硝唑，剂量为1 g/m²和2 g/m²这两个水平之一，4小时后静脉注射环磷酰胺。每21天重复一个周期。每种治疗方案中米索硝唑的剂量保持不变，但环磷酰胺的剂量范围为0.4 g/m²至1.3 g/m²。35例晚期实体瘤患者的38次试验被认为可评估。剂量限制性毒性为环磷酰胺剂量为1 g/m²时出现的粒细胞减少，无明显血小板减少或贫血。周围神经病变可忽略不计。2例患者接受了累积剂量为8 g/m²和16 g/m²的米索硝唑，未出现神经毒性。1例患者发生出血性膀胱炎。恶心和呕吐为轻至中度。3例患者可见肿瘤稳定的可能证据，1例患者有混合反应。米索硝唑的平均血清半衰期为11.3小时（范围8.4至20.0），环磷酰胺为8.3小时（范围3.2至15.5），均在先前报道的范围内。总之，该联合用药似乎耐受性良好，米索硝唑不会显著增强环磷酰胺引起的骨髓毒性或改变其药代动力学。在使用该给药方案的II期试验中，米索硝唑和环磷酰胺的推荐起始剂量分别应为2 g/m²和1 g/m²，环磷酰胺可根据个体耐受性增加剂量。
