© 1997 by Oxford University Press
Journal Of The National Cancer Institute, Vol 89, 1789-1796, Copyright © 1997 by Oxford University Press
HH Bailey, G Ripple, KD Tutsch, RZ Arzoomanian, D Alberti, C Feierabend, D Mahvi, J Schink, M Pomplun, RT Mulcahy and G Wilding
BACKGROUND: Increased intracellular glutathione has long been associated
with tumor cell resistance to various cytotoxic agents. An inhibitor of
glutathione biosynthesis, L-S,R-buthionine sulfoximine (BSO), has been
shown to enhance the cytotoxicity of chemotherapeutic agents in vitro and
in vivo. We performed a phase I study of BSO administered with the
anticancer drug melphalan to determine the combination's
safety/tolerability and to determine clinically whether BSO produced the
desired biochemical end point of glutathione depletion (<10% of
pretreatment value). METHODS: Twenty-one patients with advanced cancers
received an initial 30-minute infusion of BSO totaling 3.0 g/m2 and
immediately received a continuous infusion of BSO on one of the following
schedules: 1) 0.75 g/m2 per hour for 24 hours (four patients); 2) the same
dose rate for 48 hours (four patients); 3) the same dose rate for 72 hours
(10 patients); or 4) 1.5 g/m2 per hour for 48 hours (three patients).
During week 1, the patients received BSO alone; during weeks 2 or 3, they
received BSO plus melphalan (15 mg/m2); thereafter, the patients received
BSO plus melphalan every 4 weeks. Glutathione concentrations in peripheral
blood lymphocytes were determined for all patients; in 10 patients on three
of the administration schedules, these measurements were made in multiple
sections from tumor biopsy specimens taken before, during, and after
continuous-infusion BSO. RESULTS: Continuous-infusion BSO alone produced
minimal toxic effects, although BSO plus melphalan produced occasional
severe myelosuppression (grade 4) and frequent low-grade nausea/vomiting
(grade 1-2). This treatment also produced consistent, profound glutathione
depletion (<10% of pretreatment value). The degree of glutathione
depletion in peripheral lymphocytes was considerably less than that
observed in tumor sections. CONCLUSIONS: Continuous- infusion BSO is
relatively nontoxic and results in depletion of tumor glutathione.
ARTICLES
Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan
Department of Medicine, University of Wisconsin Comprehensive Cancer Center, Madison 53792, USA. hhbailey@facstaff.wisc.edu
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