Tetef M, Margolin K, Ahn C, Akman S, Chow W, Coluzzi P, Leong L, Morgan R J, Raschko J, Shibata S
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010.
J Cancer Res Clin Oncol. 1995;121(2):103-6. doi: 10.1007/BF01202221.
A phase II trial of menadione (2.5 g/m2 as a continuous intravenous infusion over 48 h) followed by mitomycin C (10-20 mg/m2 i.v. bolus) administered every 4-6 weeks was performed in 43 patients with advanced gastrointestinal cancer. Menadione, a vitamin K analog that lowers intracellular pools of reduced glutathione, was combined with mitomycin C in an attempt to overcome thiol-mediated resistance to alkylating-agent chemotherapy. The median age of patients entered on this trial was 58 years; performance status ranged from 60%-100%. None of the 43 evaluable patients obtained an objective response to this combination regimen. Median survival was 6.6 months. Treatment with menadione and mitomycin C was reasonably well tolerated except for hematological toxicity. A total of 27% of treatment courses were complicated by grade 3 or 4 hematological toxicity including one episode of hemolytic anemia and one episode of hemolytic uremic syndrome. One patient developed irreversible interstitial pneumonitis, and 1 patient had an asymptomatic decrease in the left-ventricular ejection fraction. Despite preclinical evidence indicating that menadione pretreatment enhances the cytotoxicity of mitomycin C, our study documents the resistance of advanced gastrointestinal cancers, particularly colorectal cancer, to mitomycin C modulated by menadione.
对43例晚期胃肠道癌患者进行了一项II期试验，采用维生素K3（2.5 g/m²，持续静脉输注48小时），随后每4 - 6周静脉推注丝裂霉素C（10 - 20 mg/m²）。维生素K3是一种维生素K类似物，可降低细胞内还原型谷胱甘肽水平，将其与丝裂霉素C联合使用，试图克服硫醇介导的对烷化剂化疗的耐药性。参与该试验的患者中位年龄为58岁；体能状态为60% - 100%。43例可评估患者中无一例对该联合方案获得客观缓解。中位生存期为6.6个月。除血液学毒性外，维生素K3和丝裂霉素C的治疗耐受性较好。共有27%的疗程出现3级或4级血液学毒性并发症，包括1例溶血性贫血和1例溶血尿毒综合征。1例患者发生不可逆的间质性肺炎，1例患者左心室射血分数无症状下降。尽管临床前证据表明维生素K3预处理可增强丝裂霉素C的细胞毒性，但我们的研究证明晚期胃肠道癌，尤其是结直肠癌，对维生素K3调节的丝裂霉素C具有耐药性。
