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Influence of Glutamine on the Growth of Human Glioma and Medulloblastoma in Culture¹

Departments of Pathology (Neuropathology) [G. D., H. S. F., D. D. B.], Medicine [G. B. E.], Pediatrics [H. S. F.], and Pharmacology [G. B. E.], Duke University Medical Center, Durham, North Carolina 27710, and Department of Neurology [G. L. C.], The Graduate Hospital, Philadelphia, Pennsylvania 19146

Cellular supply of glutamine, an essential substrate for growth, is derived from extracellular fluid and de novo synthesis. We investigated the relative importance of these sources to the growth of six human anaplastic glioma- and one human medulloblastoma-derived permanent cell lines. Exogenous glutamine was limiting for the proliferation of glioma-derived lines D-54 MG, U-118 MG, and U-251 MG. In contrast, medulloblastoma-derived line TE-671 and glioma-derived lines U-373 MG, D-245 MG, and D-259 MG grew in the absence of supplemental glutamine. Two cell lines with contrasting glutamine requirements, D-54 MG and TE-671, were used to explore the pharmacological interference with glutamine metabolism. DL--Aminoadipic acid, a reported glutamic acid analogue with gliotoxic properties, significantly inhibited the growth of both lines. These effects were reversed by increasing glutamine, suggesting that the major action of DL--aminoadipic acid is as a glutamine antagonist. In contrast, the glutamine synthetase inhibitor -hydroxylysine demonstrated activity only against TE-671. Acivicin and 6-diazo-5-oxo-L-norleucine, glutamine analogues available for clinical use, reduced the proliferation of both cell lines at pharmacological concentrations. Methionine sulfoximine, a glutamine synthetase inhibitor previously used clinically, produced marked growth inhibition only against TE-671. These findings indicate that the synthesis and utilization of glutamine are potentially exploitable targets for the chemotherapy of some human gliomas and medulloblastomas.

¹ This work was supported by NIH Grants PO1 NSCA 200023-01 and CA 11898, Duke Comprehensive Cancer Center Developments Funds (CA 14236), and the W. W. Smith charitable trust.

² Recipient of an Association for Brain Tumor Research Fellowship in memory of Bryce Davis and an American Cancer Society Junior Clinical Faculty Fellowship.

³ To whom requests for reprints should be addressed.

Received 10/12/84. Revised 4/ 3/85. Accepted 5/22/85.

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