Phase I trial of buthionine sulfoximine in combination with melphalan in patients with cancer.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
O'Dwyer
P J
PJ
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Hamilton
T C
TC
LaCreta
F P
FP
Gallo
J M
JM
Kilpatrick
D
D
Halbherr
T
T
Brennan
J
J
Bookman
M A
MA
Hoffman
J
J
Young
R C
RC
Comis
R L
RL
Ozols
R F
RF
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D001853:Bone Marrow / Q000187:drug effects; D019328:Buthionine Sulfoximine; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005978:Glutathione / Q000097:blood / Q000187:drug effects; D006801:Humans; D016014:Linear Models; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D008717:Methionine Sulfoximine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009364:Neoplasm Recurrence, Local / Q000000981:diagnostic imaging / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D009504:Neutrophils / Q000187:drug effects; D011859:Radiography; D014839:Vomiting / Q000139:chemically induced
D000964:Antimetabolites, Antineoplastic; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione; D008558:Melphalan