Gandhi V, Estey E, Du M, Keating M J, Plunkett W
Departments of Clinical Investigation and Hematology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Clin Cancer Res. 1997 Sep;3(9):1539-45.
1-beta-d-Arabinofuranosylcytosine (ara-C), an effective drug for acute leukemias, must be phosphorylated to its 5'-triphosphate, ara-CTP, for activity. Our previous studies during therapy of acute myelogenous leukemia (AML) patients demonstrated that the accumulation of ara-CTP in circulating leukemia blasts was increased by a median of 2-fold when fludarabine (30 mg/m2/day over 30 min) was infused 4 h prior to intermediate dose ara-C. The augmentation was dependent on the cellular concentration of fludarabine triphosphate (F-ara-ATP). To determine the lowest dose of fludarabine needed for modulation of ara-C metabolism, the present study administered fludarabine at a test dose (15 mg/m2 over 30 min) followed by 2 g/m2 ara-C infused over 4 h. The next day, the fludarabine/ara-C couplet was repeated but with a standard dose (30 mg/m2) of fludarabine. There was a dose-dependent accumulation of F-ara-ATP in circulating leukemia blasts; the median peak concentrations were 33 and 41 microM with 15 and 30 mg/m2 of fludarabine, respectively. These intracellular levels of F-ara-ATP effectively increased ara-CTP accumulation to similar levels. To further titrate the dose of fludarabine, the next cohort of patients (n = 4) initially received fludarabine test doses of 7.5 or 5 mg/m2, followed by the 30 mg/m2 dose of fludarabine on the next day; each dose was infused 4 h prior to 2 g/m2 of ara-C. The peak levels of F-ara-ATP at 7.5 and 5 mg/m2 fludarabine were between 3 and 39 microM. The AML blasts that achieved >/=10 microM intracellular F-ara-ATP accumulated ara-CTP similar to the levels achieved after 30 mg/m2 of fludarabine. However, <10 microM intracellular F-ara-ATP resulted in less ara-CTP accumulation compared to that observed after the conventional dose of fludarabine. These data suggest that the modulation of the ara-CTP accumulation by fludarabine is dependent on the cellular concentration of F-ara-ATP, and that 15 mg/m2 fludarabine infused over 30 min consistently produces cellular F-ara-ATP levels that maximize ara-CTP accumulation in AML blasts. These findings point to the feasibility of intensifying the fludarabine-ara-C regimen by using fludarabine as a 15 mg/m2/dose twice daily with intermediate-dose ara-C.
1-β-D-阿拉伯呋喃糖基胞嘧啶（阿糖胞苷，ara-C）是治疗急性白血病的一种有效药物，必须磷酸化为其5'-三磷酸形式阿糖胞苷三磷酸（ara-CTP）才有活性。我们之前在急性髓系白血病（AML）患者治疗期间的研究表明，在给予中等剂量阿糖胞苷前4小时输注氟达拉滨（30mg/m²，30分钟内输完）时，循环白血病原始细胞中ara-CTP的蓄积量平均增加2倍。这种增加依赖于三磷酸氟达拉滨（F-ara-ATP）的细胞内浓度。为了确定调节阿糖胞苷代谢所需的最低氟达拉滨剂量，本研究先给予氟达拉滨试验剂量（15mg/m²，30分钟内输完），随后4小时内输注2g/m²阿糖胞苷。次日，重复氟达拉滨/阿糖胞苷联合用药，但氟达拉滨采用标准剂量（30mg/m²）。循环白血病原始细胞中F-ara-ATP呈剂量依赖性蓄积；15mg/m²和30mg/m²氟达拉滨时的平均峰值浓度分别为33μM和41μM。这些细胞内F-ara-ATP水平有效地将ara-CTP蓄积量提高到相似水平。为了进一步滴定氟达拉滨剂量，下一组患者（n = 4）最初接受7.5mg/m²或5mg/m²的氟达拉滨试验剂量，次日接受30mg/m²的氟达拉滨剂量；每次剂量均在2g/m²阿糖胞苷前4小时输注。7.5mg/m²和5mg/m²氟达拉滨时F-ara-ATP的峰值水平在3至39μM之间。细胞内F-ara-ATP≥10μM的AML原始细胞蓄积ara-CTP的水平与30mg/m²氟达拉滨后达到的水平相似。然而，细胞内F-ara-ATP＜10μM时，与传统剂量氟达拉滨后相比，ara-CTP蓄积量较少。这些数据表明，氟达拉滨对ara-CTP蓄积的调节依赖于F-ara-ATP的细胞内浓度，并且30分钟内输注15mg/m²氟达拉滨持续产生的细胞内F-ara-ATP水平可使AML原始细胞中的ara-CTP蓄积量最大化。这些发现表明了通过每日两次使用15mg/m²/剂量的氟达拉滨与中等剂量阿糖胞苷强化氟达拉滨-阿糖胞苷方案的可行性。
