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Cyclophosphamide Resistance in Medulloblastoma¹

Departments of Pediatrics [H. S. F.] and Pathology [H. S. F., N. B., D. D. B.], and the Preuss Laboratory for Brain Tumor Research [H. S. F., D. D. B.], Duke University Medical Center, Durham, North Carolina 27710; The Johns Hopkins Oncology Center, Johns Hopkins University, Baltimore, Maryland 21205 [O. M. C., S. H. K., S. M. L.]; and the Department of Biochemistry, Cornell University Medical College, New York, New York 10021 [O. W. G.]

Mechanisms of tumor resistance to 4-hydroperoxycyclophosphamide (4-HC) were studied by using a panel of human medulloblastoma cell lines either passaged in the laboratory for resistance to 4-HC or established from tumors showing clinical resistance to cyclophosphamide. Multiple distinct mechanisms of resistance were demonstrated. Daoy (4-HCR), a line that was 6-fold more resistant than Daoy, contained elevated levels of aldehyde dehydrogenase (ALDH). Most of the difference in sensitivity between the Daoy (4-HCR) and Daoy cell lines was abolished when 4-HC was replaced with phenylketocyclophosphamide, a 4-HC analogue that cannot be detoxified by ALDH. Thus, elevated levels of ALDH appear to play a role in the resistance of Daoy (4-HCR). Several of the cell lines [D283 Med (4-HCR), D341 Med (4-HCR), Daoy (4-HCR), D458 Med] contained elevated levels of glutathione (GSH). No changes in glutathione-S-transferase activity or isozyme pattern were observed, but in two of these three lines, the elevation in GSH was accompanied by elevated levels of -glutamyl transpeptidase. To confirm the role of elevated GSH content in 4-HC resistance, the sensitivity of the cell lines to 4-HC was repeated after depletion of GSH by treatment with L-buthionine-S,R-sulfoximine. In medulloblastoma cell lines without other mechanisms of resistance, a linear relationship was seen between GSH content and resistance to 4-HC. Moreover, cells with GSH content >5 nmol/mg protein and no other overriding mechanism of resistance could be sensitized to 4-HC treatment with L-buthionine-S,R-sulfoximine. Finally, D283 Med (4-HCR) cells had mild elevations in both ALDH and GSH content, but were resistant to phenylketocyclophosphamide and were not significantly sensitized by L-buthionine-S,R-sulfoximine. This cell line appears to demonstrate a third mechanism of resistance to 4-HC. These results suggest that 4-HC resistance in medulloblastoma can be multifactorial.

¹ This work was supported by NIH Grants CA 44640, DK 26912, NS 00958, CA 11898, NS 20023, CA 56115, and CA 11898, Bristol-Myers Squibb Grant 100-R18, and American Cancer Society Grant CH-403C.

² To whom requests for reprints should be addressed, at Duke University Medical Center, Department of Hematology/Oncology, Box 2916, Durham, NC 27710.

³ Supported by the American Cancer Society Clinical Oncology Career Development Award.

Received 5/13/92. Accepted 7/20/92.

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