Bailey H H, Mulcahy R T, Tutsch K D, Arzoomanian R Z, Alberti D, Tombes M B, Wilding G, Pomplun M, Spriggs D R
Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, Madison 53792.
J Clin Oncol. 1994 Jan;12(1):194-205. doi: 10.1200/JCO.1994.12.1.194.
A phase I dose-escalation trial of intravenous (IV) L-buthionine-SR-sulfoximine (BSO) with melphalan (L-PAM) was performed to determine the toxicity and biologic activity of BSO, administered as a short infusion every 12 hours, and the combination of BSO plus L-PAM.
Twenty-eight patients with refractory malignancies received 30-minute infusions of BSO every 12 hours for 6 to 10 doses in week 1 followed in week 2 by either IV L-PAM (15 mg/m2) alone or BSO as in week 1 with L-PAM. Patients received the combination in week 5 (course no. 2) if they received L-PAM alone during week 2 and vice versa. BSO doses ranged from 1.5 g/m2 to 13.104 g/m2.
The only toxicity observed with BSO infusions was occasional nausea/vomiting. Evaluation of 23 paired courses (L-PAM plus BSO v L-PAM) showed significantly (P < .001) greater leukopenia and thrombocytopenia with L-PAM plus BSO. No other significant toxicity was noted. Measurement of intracellular glutathione (GSH) levels in peripheral mononuclear cells (PBLs) of all patients receiving BSO showed a consistent, non-dose-dependent, linear decrease in GSH with repeated BSO doses. Maximal GSH depletion (40% of baseline values, absolute values 200 to 250 ng/10(6) PBLs) was noted after the sixth BSO dose; extended BSO dosing schedules beyond six total BSO doses did not further deplete GSH. Evaluation of gamma-glutamylcysteine synthetase (GCS) activity showed marked inhibition near the end of each infusion with near complete recovery of GCS activity before the next BSO dose. The pattern of GCS inhibition mirrored the plasma BSO concentrations with peak values (level 6, 4 to 8 mmol/L L,R+L,S BSO) observed at the end of the infusion with a rapid decrease in plasma concentrations with an estimated half-life (t1/2) of less than 2 hours. Differential elimination of the R+S stereoisomers was observed. Analysis of L-PAM pharmacokinetics showed marked interpatient variability and a significant decrease in total-body clearance (P = .01) and volume of distribution (P = .03) in courses with L-PAM plus BSO as compared with L-PAM alone.
This study shows that BSO alone and in combination with L-PAM can be safely given to patients, but that a schedule of short infusions every 12 hours does not result in GSH depletion less than 30% of baseline values.
进行一项静脉注射（IV）L-丁硫氨酸-SR-亚砜亚胺（BSO）联合美法仑（L-PAM）的I期剂量递增试验，以确定每12小时短时间输注的BSO以及BSO加L-PAM联合用药的毒性和生物学活性。
28例难治性恶性肿瘤患者在第1周每12小时接受30分钟的BSO输注，共6至10剂，第2周接受单独静脉注射L-PAM（15mg/m²）或第1周的BSO联合L-PAM。如果患者在第2周单独接受L-PAM，则在第5周（疗程2）接受联合用药，反之亦然。BSO剂量范围为1.5g/m²至13.104g/m²。
BSO输注观察到的唯一毒性是偶尔出现恶心/呕吐。对23对疗程（L-PAM加BSO对比L-PAM）的评估显示，L-PAM加BSO组的白细胞减少和血小板减少显著更严重（P<.001）。未观察到其他显著毒性。对所有接受BSO的患者外周血单核细胞（PBLs）中细胞内谷胱甘肽（GSH）水平的测量显示，随着BSO重复给药，GSH呈持续、非剂量依赖性的线性下降。在第6次BSO给药后观察到最大GSH耗竭（基线值的40%，绝对值200至250ng/10⁶PBLs）；超过6次总BSO剂量的延长BSO给药方案并未进一步消耗GSH。对γ-谷氨酰半胱氨酸合成酶（GCS）活性的评估显示，每次输注接近结束时GCS活性受到显著抑制，在下一次BSO给药前GCS活性几乎完全恢复。GCS抑制模式与血浆BSO浓度相似，在输注结束时观察到峰值（6级，4至8mmol/L L，R+L，S BSO），血浆浓度迅速下降，估计半衰期（t1/2）小于2小时。观察到R+S立体异构体的差异消除。L-PAM药代动力学分析显示，与单独使用L-PAM相比，L-PAM加BSO疗程中患者间变异性显著，全身清除率显著降低（P=.01），分布容积显著降低（P=.03）。
本研究表明，单独使用BSO以及BSO与L-PAM联合用药对患者是安全的，但每12小时短时间输注的方案不会导致GSH耗竭低于基线值的30%。
