Inhibition of the protective effect of cyclophosphamide by pre-treatment with buthionine sulfoximine

James Carmichael (Lead / Corresponding author), Norman Friedman, Zelig Tochner, David J. Adams, C. Roland Wolf, James B. Mitchell, Angelo Russo

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Low dose cyclophosphamide (CTX) is protective against a subsequent challenge with a lethal dose of the same drug administered 5 days later. At the time of maximal protection, elevation of glutathione (GSH) and glutathione transferase (GST) levels are detectable in the bone marrow of pre-treated animals. Elevation of GSH levels in the bone marrow was inhibited with the use of D,L-buthionine-S,R-sulfoximine (BSO), and this resulted in loss of the protective effect of CTX pre-treatment. In contrast, the overshoot in GST levels observed in these animals was not affected by BSO therapy. Bone marrow GSH levels in animals treated with BSO alone were minimally depleted (68% of control); whereas, animals pre-treated with CYX followed by BSO exhibited a greater reduction in GSH levels (47% of control). These results suggest that GSH is important in the protective effect afforded by low dose CTX pre-treatment and that the elevation of GSH levels observed is the result of a rebound synthetic process. In CTX pre-treated animals, BSO treatment resulted in greater than predicted depletion in GSH levels, and, therefore, caution is recommended with the potential use of combinations of BSO and cytotoxic drugs in the presence of a regenerating bone marrow.

Original languageEnglish
Pages (from-to)1191-1193
Number of pages3
JournalInternational Journal of Radiation Oncology, Biology, Physics
Volume12
Issue number7 PART 1
DOIs
Publication statusPublished - 1 Jul 1986

Keywords

  • Bone marrow
  • Buthionine sulfoximine
  • Cyclophosphamide
  • Glutathione
  • Glutathione transferases

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