Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan

Howard H. Bailey*, Greg Ripple, Kendra D. Tutsch, Rhoda Z. Arzoomanian, Dona Alberti, Chris Feierabend, David Mahvi, Julian Schink, Marcia Pomplun, R. Timothy Mulcahy, George Wilding

*Corresponding author for this work

Research output: Contribution to journalArticle

124 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1789-1796
Number of pages8
JournalJournal of the National Cancer Institute
Volume89
Issue number23
DOIs
StatePublished - Dec 3 1997

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Bailey, H. H., Ripple, G., Tutsch, K. D., Arzoomanian, R. Z., Alberti, D., Feierabend, C., Mahvi, D., Schink, J., Pomplun, M., Mulcahy, R. T., & Wilding, G. (1997). Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan. Journal of the National Cancer Institute, 89(23), 1789-1796. https://doi.org/10.1093/jnci/89.23.1789