Abbruzzese J L, Grunewald R, Weeks E A, Gravel D, Adams T, Nowak B, Mineishi S, Tarassoff P, Satterlee W, Raber M N
Department of Medical Oncology, University of Texas MD Anderson Cancer Center, Houston 77030.
J Clin Oncol. 1991 Mar;9(3):491-8. doi: 10.1200/JCO.1991.9.3.491.
A novel deoxycytidine analog, gemcitabine (2',2'-difluorodeoxycytidine [dFdC]), has been studied in a phase I clinical and pharmacology trial. Doses ranging from 10 to 1,000 mg/m2 were administered over 30 minutes weekly times 3 weeks every 4 weeks. The maximum-tolerated dose (MTD) was 790 mg/m2. The dose-limiting toxicity was myelosuppression, with thrombocytopenia and anemia quantitatively more important than granulocytopenia. Nonhematologic toxicity was minimal. Two responses in patients with adenocarcinomas of the colon and lung were documented. The maximum dFdC plasma concentration, reached after 15 minutes of infusion, was proportional to the total dose administered. Elimination, due mainly to deamination, was rapid (terminal half-life [t1/2], 8.0 minutes) and dose independent. The deamination product 2',2'-difluorodeoxyuridine (dFdU) was eliminated with biphasic kinetics characterized by a long terminal phase (t1/2, 14 hours); it was the sole metabolite detected in urine. The concentration of dFdC 5'-triphosphate in circulating mononuclear cells increased in proportion to the dFdC dose at infusions between 35 and 250 mg/m2. No further increment in dFdC 5'-triphosphate (dFdCTP) was observed at higher doses, which resulted in plasma dFdC concentrations greater than 20 mumol/L (350 to 1,000 mg/m2), suggesting saturation of dFdC 5'-phosphate accumulation. The recommended dose for phase II clinical trials in solid tumors is 790 mg/m2/wk.
一种新型脱氧胞苷类似物吉西他滨（2'，2'-二氟脱氧胞苷 [dFdC]）已在一项 I 期临床和药理学试验中进行了研究。剂量范围为 10 至 1000 mg/m²，在 30 分钟内静脉输注，每周 1 次，共 3 周，每 4 周重复。最大耐受剂量（MTD）为 790 mg/m²。剂量限制性毒性为骨髓抑制，血小板减少和贫血在数量上比粒细胞减少更重要。非血液学毒性极小。记录到 2 例结肠和肺癌腺癌患者出现缓解。输注 15 分钟后达到的 dFdC 血浆最大浓度与给药总剂量成正比。主要由于脱氨作用导致的消除很快（终末半衰期 [t1/2]，8.0 分钟）且与剂量无关。脱氨产物 2'，2'-二氟脱氧尿苷（dFdU）以双相动力学消除，其特征为长终末相（t1/2，14 小时）；它是尿液中检测到的唯一代谢产物。在 35 至 250 mg/m² 的输注剂量下，循环单核细胞中 dFdC 5'-三磷酸的浓度与 dFdC 剂量成正比增加。在更高剂量（导致血浆 dFdC 浓度大于 20 μmol/L [350 至 1000 mg/m²]）下未观察到 dFdC 5'-三磷酸（dFdCTP）的进一步增加，这表明 dFdC 5'-磷酸积累已饱和。实体瘤 II 期临床试验的推荐剂量为 790 mg/m²/周。
