Touroutoglou N, Gravel D, Raber M N, Plunkett W, Abbruzzese J L
Department of Gastrointestinal Medical Oncology and Digestive Diseases, University of Texas, M.D. Anderson Cancer Center, Houston, USA.
Ann Oncol. 1998 Sep;9(9):1003-8. doi: 10.1023/A:1008487932384.
The long intracellular half-life of gemcitabine's active metabolite, difluorodeoxycytidine triphosphate (dFdCTP), suggested that small increases in peak intracellular dFdCTP levels would have a profound effect on its intracellular area under the curve (AUC). Previous studies had shown that a dose rate of 10 mg/m2/min that achieved plasma gemcitabine concentrations of 15-20 mumol/l maximized the intracellular rate of accumulation of dFdCTP. This phase I study was therefore designed to evaluate the clinical feasibility of this pharmacologically-based strategy; assessing the toxic effects and anticancer activity of high weekly doses of gemcitabine administered at a fixed dose rate of 10 mg/m2/min.
Thirty one patients with solid tumor malignancies received 103 courses of gemcitabine. Twenty nine patients had received prior treatment. Weekly doses were escalated from 1200 mg/m2 administered intravenously over 120 minutes to 2800 mg/m2 over 280 minutes for three weeks every four weeks.
The first-course MTD was 2250 mg/m2. The dose-limiting toxicity was myelosuppression with thrombocytopenia and granulocytopenia quantitatively more important than anemia. However, cumulative myelosuppression was documented suggesting that a lower MTD of 1800 mg/m2 was more appropriate with a recommended phase II starting dose of 1500 mg/m2. There was no neurologic toxicity. Nonhematologic toxicity was minimal and included fatigue, nausea, and skin rash, but was not dose dependent. Three objective responses were documented.
Escalated doses of gemcitabine designed to maximize intracellular dFdCTP levels can be safely administered using a fixed dose rate. The encouraging anticancer effects documented in patients with refractory malignancies suggests that short gemcitabine infusions based on well-established cellular pharmacologic principles may improve the therapeutic index of this agent. Comparison with standard 30-minute bolus dosing will be evaluated in subsequent randomized phase II trials.
吉西他滨的活性代谢产物二氟脱氧胞苷三磷酸（dFdCTP）在细胞内的半衰期较长，这表明细胞内dFdCTP峰值水平的小幅升高将对其细胞内曲线下面积（AUC）产生深远影响。先前的研究表明，剂量率为10mg/m²/分钟，使血浆吉西他滨浓度达到15 - 20μmol/L时，可使dFdCTP的细胞内积累速率最大化。因此，本I期研究旨在评估这种基于药理学策略的临床可行性；评估以10mg/m²/分钟的固定剂量率每周给予高剂量吉西他滨的毒性作用和抗癌活性。
31例实体瘤恶性肿瘤患者接受了103个疗程的吉西他滨治疗。29例患者曾接受过先前治疗。每周剂量从静脉输注120分钟的1200mg/m²逐步增加到280分钟的2800mg/m²，每四周进行三周治疗。
第一疗程的最大耐受剂量（MTD）为2250mg/m²。剂量限制性毒性为骨髓抑制，血小板减少和粒细胞减少在数量上比贫血更重要。然而，有累积骨髓抑制的记录，表明较低的MTD为1800mg/m²更合适，推荐的II期起始剂量为1500mg/m²。没有神经毒性。非血液学毒性最小，包括疲劳、恶心和皮疹，但不依赖剂量。记录到3例客观缓解。
设计用于最大化细胞内dFdCTP水平的递增剂量吉西他滨可以使用固定剂量率安全给药。难治性恶性肿瘤患者中记录到的令人鼓舞的抗癌效果表明，基于成熟细胞药理学原理的短时间吉西他滨输注可能会提高该药物的治疗指数。与标准30分钟推注给药的比较将在随后的随机II期试验中进行评估。
