Masuda N, Matsui K, Yamamoto N, Nogami T, Nakagawa K, Negoro S, Takeda K, Takifuji N, Yamada M, Kudoh S, Okuda T, Nemoto S, Ogawa K, Myobudani H, Nihira S, Fukuoka M
Department of Internal Medicine, Osaka Prefectural Habikino Hospital, Japan.
Clin Cancer Res. 2000 Jun;6(6):2288-94.
2'-deoxy-2'-methylidenecytidine (DMDC) is a potent deoxycytidine analogue. Preclinical studies of DMDC demonstrated activity against a variety of murine and human tumors in cell cultures and murine models and indicate enhanced antitumor activity of DMDC when it was administered in a manner that provided prolonged systemic exposure. In view of this observation, this study was designed to determine the toxicities, maximum-tolerated dose, and pharmacokinetic profile of DMDC. DMDC was given p.o. under fasting conditions for 14 consecutive days every 4 weeks in patients with advanced solid tumors. The starting dose was 12 mg/m2/day. Pharmacokinetic studies were carried out on days 1 and 14 of the first cycle. Fourteen patients received 22 courses of DMDC. The dose-limiting toxicities were anorexia, leukopenia, thrombocytopenia, and anemia. General fatigue was the common nonhematological toxicity. The maximum-tolerated dose was 18 mg/m2/day, at which two of six patients developed grade 3 toxicities. This dose level could also be considered for Phase II testing with this schedule. At the 18-mg/m2/day dose level, the mean terminal half-life, maximum plasma concentration (Cmax), the area under the plasma drug concentration-time curve (AUC(0-infinity)) on day 1 were 1.7496 h, 112.9 ng/ml, and 399.8 ng x h/ml, respectively. Forty to 50% of the administered dose was recovered in the urine, indicating a good bioavailability and resulting significant systemic exposure to the drug, which may enable chronic oral treatment.
2'-脱氧-2'-亚甲基胞苷（DMDC）是一种强效的脱氧胞苷类似物。DMDC的临床前研究表明，它在细胞培养和小鼠模型中对多种小鼠和人类肿瘤具有活性，并表明当以提供长时间全身暴露的方式给药时，DMDC的抗肿瘤活性增强。鉴于这一观察结果，本研究旨在确定DMDC的毒性、最大耐受剂量和药代动力学特征。对于晚期实体瘤患者，每4周在禁食条件下口服DMDC连续14天。起始剂量为12mg/m²/天。在第一个周期的第1天和第14天进行药代动力学研究。14名患者接受了22个疗程的DMDC治疗。剂量限制性毒性为厌食、白细胞减少、血小板减少和贫血。全身乏力是常见的非血液学毒性。最大耐受剂量为18mg/m²/天，在此剂量下，6名患者中有2名出现3级毒性。该剂量水平也可考虑用于该方案的II期试验。在18mg/m²/天的剂量水平下，第1天的平均终末半衰期、最大血浆浓度（Cmax）、血浆药物浓度-时间曲线下面积（AUC(0-∞)）分别为1.7496小时、112.9ng/ml和399.8ng·h/ml。给药剂量的40%至50%在尿液中回收，表明生物利用度良好，药物全身暴露显著，这可能使慢性口服治疗成为可能。
