Gandhi V, Plunkett W, Rodriguez C O, Nowak B J, Du M, Ayres M, Kisor D F, Mitchell B S, Kurtzberg J, Keating M J
Department of Clinical Investigation, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
J Clin Oncol. 1998 Nov;16(11):3607-15. doi: 10.1200/JCO.1998.16.11.3607.
In vitro investigations with arabinosylguanine (ara-G) demonstrated potent cytotoxicity to T-lymphoblastoid cell lines. The goals of the present study were to evaluate GW506U78, a prodrug of ara-G, against human hematologic malignancies and to determine its pharmacokinetics in plasma and cells.
During a phase I multicenter trial of GW506U78, 26 patients were treated at M.D. Anderson Cancer Center (MDACC). Daily doses between 20 and 60 mg/kg were administered for 5 days. Parallel plasma and cellular pharmacokinetic studies were conducted.
Complete (n=5) or partial remission (n=5) was achieved in T-cell acute lymphoblastic leukemia (T-ALL), T-lymphoid blast crisis, T-lymphoma, and B-cell chronic lymphocytic leukemia (B-CLL) (n=13). In contrast, patients with B-ALL, B-lymphoma, acute myelogenous leukemia (AMI), or T-CLL did not respond. Peak plasma concentrations of GW506U78 and ara-G were dose-dependent. The elimination of GW506U78 (half-life [t1/2]=17 minutes) was faster than the elimination of ara-G (t1/2=3.7 hours). Median peak concentrations of ara-GTP were 23, 42, 85, and 93 micromol/L at 20, 30, 40, and 60 mg/kg, respectively. T-lymphoblasts accumulated significantly (P=.0008) higher peak arabinsylguanosine triphosphate (ara-GTP) (median, 140 micromol/L; n=7) compared with other diagnoses (median, 50 micromol/L; n=9) and normal mononuclear cells (n=3). The ara-GTP elimination was slow in all diagnoses (median, > 24 hours). Responders accumulated significantly (P=.0005) higher levels of ara-GTP (median, 157 micromol/L) compared with patients who failed to respond (median, 44 micromol/L).
GW506U78 is an effective prodrug and a potent agent for hematologic malignancies with major efficacy in T-cell diseases. The pharmacokinetics of ara-GTP in leukemia cells are strongly correlated with clinical responses to GW506U78.
对阿糖鸟嘌呤（ara-G）进行的体外研究表明，其对T淋巴母细胞系具有强大的细胞毒性。本研究的目的是评估ara-G的前体药物GW506U78对人类血液系统恶性肿瘤的疗效，并确定其在血浆和细胞中的药代动力学。
在GW506U78的I期多中心试验中，26例患者在MD安德森癌症中心（MDACC）接受治疗。每日剂量为20至60mg/kg，持续给药5天。同时进行了血浆和细胞药代动力学研究。
T细胞急性淋巴细胞白血病（T-ALL）、T淋巴母细胞危象、T淋巴瘤和B细胞慢性淋巴细胞白血病（B-CLL）（n = 13）患者实现了完全缓解（n = 5）或部分缓解（n = 5）。相比之下，B-ALL、B淋巴瘤、急性髓性白血病（AML）或T-CLL患者无反应。GW506U78和ara-G的血浆峰值浓度呈剂量依赖性。GW506U78的消除（半衰期[t1/2]=17分钟）比ara-G的消除（t1/2 = 3.7小时）更快。在20、30、40和60mg/kg剂量下，ara-GTP的中位峰值浓度分别为23、42、85和93μmol/L。与其他诊断（中位值，50μmol/L；n = 9）和正常单核细胞（n = 3）相比，T淋巴母细胞积累的阿糖鸟苷三磷酸（ara-GTP）峰值显著更高（P = 0.0008）（中位值，140μmol/L；n = 7）。在所有诊断中，ara-GTP的消除都很缓慢（中位值，> 24小时）。与未反应的患者（中位值，44μmol/L）相比，反应者积累的ara-GTP水平显著更高（P = 0.0005）（中位值，157μmol/L）。
GW506U78是一种有效的前体药物，对血液系统恶性肿瘤有效，对T细胞疾病具有主要疗效。白血病细胞中ara-GTP的药代动力学与对GW506U78的临床反应密切相关。
