Pharmacodynamics of prolonged treatment with L,S-buthionine sulfoximine

Kamal Malaker, Selwyn J. Hurwitz, Edward A. Bump, Owen W. Griffith, Leon L. Lai, Nancy Riese, C. Norman Coleman

Research output: Contribution to journalArticle

Abstract

Purpose: To develop dosing criteria for the use of L-buthionine-S-sulfoximine (active diastereoisomer) as a glutathione depletor in the clinic, using a pharmacodynamic and pharmacokinetic in vitro-in vivo approach. Methods and Materials: In vitro: L-buthionine-S-sulfoximine uptake was determined in human glioblastoma cells (T98G)and NIH-3T3 cells using 35S-labeled drug. Dose response relationships were derived for inhibition of glutathione synthesis in CHO cells, and for depletion of glutathione in exponentially growing T98G and CHO cells, as a function of extracellular L-buthionine-S-sulfoximine concentration. Steady-state glutathione levels for CHO and NIH-3T3 cells were measured using an enzymatic assay, while glutathione synthesis rates in CHO cells were determined using a flow cytometric assay. In vivo: L-buthionine-S-sulfoximine biodistribution was determined in male nude mice carrying human glioblastomas (T98G) intracranialy, using 35S-labelled drug infused subcutaneously by osmotic pump. Tissue glutathione levels were measured using an enzymatic assay. Results and Conclusion: The observed cellular uptake t 1 2 of approximately 55 min, coupled with a previously reported, rapid in vivo clearance of buthionine sulfoximine, suggest that continuous infusion would be preferable to bolus dosing. Effective concentrations of L-buthionine-S-sulfoximine (24 h exposure), required to lower cellular glutathione content to 50% of control (EC50), were under 1 rum for both cell lines. The amount of L-buthionine-S-sulfoximine in tissues (estimated from 35S drug disposition) reached steady state within 8 h and was proportional to the rate of infusion. Brain tumors were depleted to approximately 50% of control glutathione by a infusion rate of 0.25 μmoles/h (25 g mice). At lower infusion rates an increase in glutathione content was noted in certain nude mouse tissues including brain tumor xenografts.

Original languageEnglish (US)
Pages (from-to)407-412
Number of pages6
JournalInternational journal of radiation oncology, biology, physics
Volume29
Issue number2
DOIs
StatePublished - May 15 1994

Keywords

  • Buthionine sulfoximine
  • Etanidazole
  • Glioblastoma
  • Glutathione
  • γ-glutamylcysteine synthetase

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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  • Cite this

    Malaker, K., Hurwitz, S. J., Bump, E. A., Griffith, O. W., Lai, L. L., Riese, N., & Norman Coleman, C. (1994). Pharmacodynamics of prolonged treatment with L,S-buthionine sulfoximine. International journal of radiation oncology, biology, physics, 29(2), 407-412. https://doi.org/10.1016/0360-3016(94)90299-2