Margolin K A, Akman S A, Leong L A, Morgan R J, Somlo G, Raschko J W, Ahn C, Doroshow J H
Department of Medical Oncology and Therapeutic Research City of Hope National Medical Center, Duarte, CA 91010, USA.
Cancer Chemother Pharmacol. 1995;36(4):293-8. doi: 10.1007/BF00689046.
A phase I study of mitomycin C with menadione (2-methyl-1,4-naphthoquinone, a vitamin K analogue which lowers intracellular pools of reduced glutathione) was designed as an approach to overcoming tumor cell resistance to alkylating agent chemotherapy. Patients with refractory solid tumors (n = 51) were treated with a 48-h continuous intravenous infusion of menadione followed by a bolus intravenous dose of mitomycin C at the completion of the menadione infusion. Initial menadione doses of 8.0 and 4.0 g/m2 over 48 h were associated with hemolysis, so subsequent dose levels of menadione ranged from 1.0 to 3.0 g/m2 with mitomycin C from 5 to 20 mg/m2. All three patients treated with menadione at 8.0 g/m2 and the single patient treated at 4.0 g/m2 with mitomycin C at 5 mg/m2 developed clinically significant hemolysis despite the presence of red blood cell glucose-6-phosphate dehydrogenase. Subsequently, a revised escalation scheme for menadione was used, and all patients tolerated menadione doses of 1-2.5 g/m2 over 48 h with mitomycin C doses up to 20 mg/m2. Since the 3.0 g/m2 dose of menadione was associated with mild hemolysis in three of four patients, the maximum tolerated dose of menadione was established at 2.5 g/m2. All of the mitomycin dose levels were tolerated without unexpected toxicities attributable to the combination. Prolonged infusions of menadione at doses which have been associated with lowering of intracellular glutathione pools in short-term exposure are limited by dose-dependent hemolysis, probably due to depletion of erythrocyte glutathione by menadione-related redox cycling. There was no detectable deleterious effect of pre-exposure to menadione on mitomycin C tolerance. We recommend a combination of menadione at 2.5 g/m2 as a continuous intravenous infusion and mitomycin C at 15 mg/m2 for further study in solid tumors, for which treatment with single-agent mitomycin C is appropriate.
一项关于丝裂霉素C与甲萘醌（2-甲基-1,4-萘醌，一种维生素K类似物，可降低细胞内还原型谷胱甘肽池）的I期研究旨在克服肿瘤细胞对烷化剂化疗的耐药性。难治性实体瘤患者（n = 51）接受甲萘醌48小时持续静脉输注，在甲萘醌输注结束时静脉推注丝裂霉素C。最初48小时内甲萘醌剂量为8.0和4.0 g/m²与溶血有关，因此随后甲萘醌剂量水平为1.0至3.0 g/m²，丝裂霉素C剂量为5至20 mg/m²。尽管存在红细胞葡萄糖-6-磷酸脱氢酶，但接受8.0 g/m²甲萘醌治疗的所有3例患者以及接受4.0 g/m²甲萘醌和5 mg/m²丝裂霉素C治疗的1例患者均出现了具有临床意义的溶血。随后，采用了修订后的甲萘醌剂量递增方案，所有患者均耐受48小时内1-2.5 g/m²的甲萘醌剂量以及高达20 mg/m²的丝裂霉素C剂量。由于3.0 g/m²的甲萘醌剂量在4例患者中有3例出现轻度溶血，因此确定甲萘醌的最大耐受剂量为2.5 g/m²。所有丝裂霉素剂量水平均被耐受，未出现该联合用药所致的意外毒性。短期暴露时与细胞内谷胱甘肽池降低相关剂量的甲萘醌长时间输注受剂量依赖性溶血限制，这可能是由于甲萘醌相关的氧化还原循环导致红细胞谷胱甘肽耗竭。预先暴露于甲萘醌对丝裂霉素C耐受性未检测到有害影响。我们建议将2.5 g/m²甲萘醌持续静脉输注与15 mg/m²丝裂霉素C联合用于实体瘤的进一步研究，对于这些实体瘤，单药丝裂霉素C治疗是合适的。
