TY - JOUR
T1 - Phase I trial of buthionine sulfoximine in combination with melphalan in patients with cancer
AU - O'Dwyer, P. J.
AU - Hamilton, T. C.
AU - LaCreta, F. P.
AU - Gallo, J. M.
AU - Kilpatrick, D.
AU - Halbherr, T.
AU - Brennan, J.
AU - Bookman, M. A.
AU - Hoffman, J.
AU - Young, R. C.
AU - Comis, R. L.
AU - Ozols, R. F.
PY - 1996/1
Y1 - 1996/1
N2 - Purpose and Methods: 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 (IV) every 12 hours for six doses, and 1 week later the same BSO as cycle one with melphalan (L- PAM) 15 mg/m2 IV 1 hour after the fifth dose. BSO doses were escalated from 1.5 to 17 g/m2 in 41 patients. Results: The only toxicity attributable to BSO was grade I or II nausea/vomiting in 50% of patients. Dose-related neutropenia required on 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 aver 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 ≥ 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 ≥ 13 g/m2, tumor GSH was ≤ 20% of starting values an 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 (CL(t)) and volume of distribution at steady-state (V(ss)) for both isomers were dose-independent. The CL(t) of S-BSO was significantly less than that of R-BSO at all doses, but no significant differences in V(ss) were observed between the racemates. Harmonic mean half-lives were 1.39 hours and 1.89 hours for R-RSO and S-BSO, respectively. Conclusion: 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.
AB - Purpose and Methods: 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 (IV) every 12 hours for six doses, and 1 week later the same BSO as cycle one with melphalan (L- PAM) 15 mg/m2 IV 1 hour after the fifth dose. BSO doses were escalated from 1.5 to 17 g/m2 in 41 patients. Results: The only toxicity attributable to BSO was grade I or II nausea/vomiting in 50% of patients. Dose-related neutropenia required on 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 aver 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 ≥ 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 ≥ 13 g/m2, tumor GSH was ≤ 20% of starting values an 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 (CL(t)) and volume of distribution at steady-state (V(ss)) for both isomers were dose-independent. The CL(t) of S-BSO was significantly less than that of R-BSO at all doses, but no significant differences in V(ss) were observed between the racemates. Harmonic mean half-lives were 1.39 hours and 1.89 hours for R-RSO and S-BSO, respectively. Conclusion: 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.
UR - http://www.scopus.com/inward/record.url?scp=9044254931&partnerID=8YFLogxK
U2 - 10.1200/JCO.1996.14.1.249
DO - 10.1200/JCO.1996.14.1.249
M3 - Article
AN - SCOPUS:9044254931
SN - 0732-183X
VL - 14
SP - 249
EP - 256
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 1
ER -