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Rate of Buthionine Sulfoximine Entry into Brain and Xenotransplanted Human Gliomas¹

Department of Neurology, Northwestern University Medical School, Evanston Hospital, Evanston, Illinois 60201 [I. F., K. E. S., D. R. G.]; Department of Biochemistry, The New York Hospital-Cornell Medical Center, Cornell University, New York, New York 10021 [O. W. G.]; and Departments of Pathology (Neuropathology) [D. D. B.] and Pediatrics, [H. S. F.], Duke University Medical Center, Durham, North Carolina 27710

Buthionine sulfoximine (BSO) is an inhibitor of glutathione synthesis and can be used to potentiate the effects of chemotherapeutic alkylating agents and radiotherapy. We examined the rates of influx and efflux of [³⁵S]BSO administered to athymic mice with and without xenografted D-54MG human gliomas. Three analytic approaches were applied to the experimental data to obtain values of the blood-to-tissue influx constant, K₁, of BSO. Multiple time point experiments in tumor-bearing mice were analyzed with a two-compartment model and nonlinear fitting routines, and by graphical analysis which assumed no backflux of BSO from tissue to blood. A third approach used single time point data in nontumorbearing mice and assumed no backflux. Calculated values of the K₁ of BSO ranged from 0.23 to 1.35 µl/g/min in tumor-free cortex, and from 5.3 to 6.3 µl/g/min in the D-54MG gliomas. The tissue-to-blood efflux constant, k₂, was zero in both cortex and tumor, suggesting that BSO entered cells and was trapped once it crossed the blood-brain barrier. Estimates of plasma vascular space (V_p) ranged from 2 to 20 µl/g in cortex, and from 103 to 169 µl/g in tumor. Another set of experiments, done in normal mice with different doses of BSO, suggested that BSO competes for neutral amino acid transport sites at the blood-brain barrier, but that the capacity of the carrier-mediated transport system is low and saturates at administered doses of about 0.5 mmol/kg (corresponding to plasma concentrations of about 12 µmol/ml). The rate of entry into brain was proportional to the octanol/water partition coefficient and molecular weight of BSO, which also supports passive diffusion as the means of entry. Consequently, although the rate of BSO entry into D-54MG gliomas was between 4 and 30 times higher than the rate of entry into tumor-free cortex, the results of these experiments suggest that most of the BSO that enters brain tumors in the doses commonly used in experimental situations will cross capillaries by passive diffusion.

¹ This work was supported by NIH Grants NS12745, RR03321, DK26912, NS20023, CA44640, CA11898, NS00958, American Cancer Society Grant CH-403, and by the Richard M. Lilienfeld Memorial Fund.

² Recipient of an Arlene and Marshall Bennett Fellowship in Neuro-oncology from the Division of Neurosurgery, Evanston Hospital. Present address: Department of Neurology, University Medical School of Debrecen, P.O. Box 23, H-4014 Debrecen, Hungary.

³ To whom requests for reprints should be addressed, at 2650 Ridge Avenue, Evanston, IL 60201.

Received 6/ 9/89. Revised 11/ 6/89. Accepted 11/14/89.