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
Externally publishedYes

Fingerprint

Buthionine Sulfoximine
glutathione
Glutathione
CHO Cells
cells
mice
NIH 3T3 Cells
drugs
Enzyme Assays
Glioblastoma
Nude Mice
Brain Neoplasms
brain
tumors
Pharmaceutical Preparations
clearances
synthesis
cultured cells
Heterografts
depletion

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation

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

Pharmacodynamics of prolonged treatment with L,S-buthionine sulfoximine. / Malaker, Kamal; Hurwitz, Selwyn J.; Bump, Edward A.; Griffith, Owen W.; Lai, Leon L.; Riese, Nancy; Norman Coleman, C.

In: International Journal of Radiation Oncology, Biology, Physics, Vol. 29, No. 2, 15.05.1994, p. 407-412.

Research output: Contribution to journalArticle

Malaker, K, Hurwitz, SJ, Bump, EA, Griffith, OW, Lai, LL, Riese, N & Norman Coleman, C 1994, 'Pharmacodynamics of prolonged treatment with L,S-buthionine sulfoximine', International Journal of Radiation Oncology, Biology, Physics, vol. 29, no. 2, pp. 407-412. https://doi.org/10.1016/0360-3016(94)90299-2
Malaker, Kamal ; Hurwitz, Selwyn J. ; Bump, Edward A. ; Griffith, Owen W. ; Lai, Leon L. ; Riese, Nancy ; Norman Coleman, C. / Pharmacodynamics of prolonged treatment with L,S-buthionine sulfoximine. In: International Journal of Radiation Oncology, Biology, Physics. 1994 ; Vol. 29, No. 2. pp. 407-412.
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