O'Dwyer P J, Hamilton T C, LaCreta F P, Gallo J M, Kilpatrick D, Halbherr T, Brennan J, Bookman M A, Hoffman J, Young R C, Comis R L, Ozols R F
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
J Clin Oncol. 1996 Jan;14(1):249-56. doi: 10.1200/JCO.1996.14.1.249.
Resistance to alkylating agents and platinum compounds is associated with elevated levels of glutathione (GSH). Depletion of GSH by buthionine sulfoximine (BSO) restores the sensitivity of resistant tumors to melphalan in vitro and in vivo. In a phase I trial, each patient received two cycles as follows: BSO alone intravenously (i.v.) every 12 hours for six doses, and 1 week later the same BSO as cycle one with melphalan (L-PAM) 15 mg/m2 i.v. 1 hour after the fifth dose. BSO doses were escalated from 1.5 to 17 g/m2 in 41 patients.
The only toxicity attributable to BSO was grade I or II nausea/vomiting in 50% of patients. Dose-related neutropenia required an L-PAM dose reduction to 10 mg/m2 at BSO 7.5 g/m2. We measured GSH in peripheral mononuclear cells (PMN), and in tumor biopsies when available, at intervals following BSO dosing. In PMNs, GSH content decreased over 36 to 72 hours to reach a nadir on day 3; at the highest dose, recovery was delayed beyond day 7. The mean PMN GSH nadirs were approximately 10% of control at BSO doses > or = 7.5 g/m2; at 13 and 17 g/m2, all but two patients had nadir values in this range. GSH was depleted in sequential tumor biopsies to a variable extent, but with a similar time course. At BSO doses > or = 13 g/m2, tumor GSH was < or = 20% of starting values on day 3 in five of seven patients; recovery had not occurred by day 5. We measured plasma concentrations of R- and S-BSO by high-performance liquid chromatography (HPLC) in 22 patients throughout the dosing period. Total-body clearance (CLt) and volume of distribution at steady-state (Vss) for both isomers were dose-independent. The CLt of S-BSO was significantly less than that of R-BSO at all doses, but no significant differences in Vss were observed between the racemates. Harmonic mean half-lives were 1.39 hours and 1.89 hours for R-BSO and S-BSO, respectively.
A biochemically appropriate dose of BSO for use on this schedule is 13 g/m2, which will be used in phase II trials to be conducted in ovarian cancer and melanoma.
对烷化剂和铂类化合物的耐药性与谷胱甘肽（GSH）水平升高有关。丁硫氨酸亚砜胺（BSO）消耗GSH可在体外和体内恢复耐药肿瘤对美法仑的敏感性。在一项I期试验中，每位患者接受两个周期的治疗，具体如下：单独静脉注射（i.v.）BSO，每12小时一次，共六剂；1周后，给予与第一周期相同的BSO，并在第五剂后1小时静脉注射美法仑（L-PAM）15mg/m²。41例患者的BSO剂量从1.5g/m²逐步增加至17g/m²。
归因于BSO的唯一毒性是50%的患者出现I级或II级恶心/呕吐。剂量相关的中性粒细胞减少症要求在BSO剂量为7.5g/m²时将L-PAM剂量降至10mg/m²。我们在BSO给药后的不同时间间隔测量外周血单核细胞（PMN）中的GSH，如有肿瘤活检样本也进行测量。在PMN中，GSH含量在36至72小时内下降，在第3天达到最低点；在最高剂量时，恢复延迟至第7天以后。在BSO剂量≥7.5g/m²时，PMN中GSH的平均最低点约为对照值的10%；在13g/m²和17g/m²时，除两名患者外，所有患者的最低点值均在此范围内。连续的肿瘤活检样本中的GSH在不同程度上被消耗，但时间进程相似。在BSO剂量≥13g/m²时，7例患者中有5例在第3天肿瘤GSH≤起始值的20%；到第5天尚未恢复。我们在整个给药期间通过高效液相色谱（HPLC）测量了22例患者血浆中R-BSO和S-BSO的浓度。两种异构体的全身清除率（CLt）和稳态分布容积（Vss）均与剂量无关。在所有剂量下，S-BSO的CLt均显著低于R-BSO，但两种外消旋体之间的Vss未观察到显著差异。R-BSO和S-BSO的调和平均半衰期分别为1.39小时和1.89小时。
按照此方案使用的BSO的生化适宜剂量为13g/m²用于II期试验，将在卵巢癌和黑色素瘤中进行。
