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Cyclophosphamide resistance in medulloblastoma.

Publication ,  Journal Article
Friedman, HS; Colvin, OM; Kaufmann, SH; Ludeman, SM; Bullock, N; Bigner, DD; Griffith, OW
Published in: Cancer Res
October 1, 1992

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 gamma-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 greater than 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.

Duke Scholars

Published In

Cancer Res

ISSN

0008-5472

Publication Date

October 1, 1992

Volume

52

Issue

19

Start / End Page

5373 / 5378

Location

United States

Related Subject Headings

  • gamma-Glutamyltransferase
  • Tumor Cells, Cultured
  • Sensitivity and Specificity
  • Oncology & Carcinogenesis
  • Methionine Sulfoximine
  • Medulloblastoma
  • Male
  • Infant
  • Humans
  • Glutathione Transferase
 

Citation

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Friedman, H. S., Colvin, O. M., Kaufmann, S. H., Ludeman, S. M., Bullock, N., Bigner, D. D., & Griffith, O. W. (1992). Cyclophosphamide resistance in medulloblastoma. Cancer Res, 52(19), 5373–5378.
Friedman, H. S., O. M. Colvin, S. H. Kaufmann, S. M. Ludeman, N. Bullock, D. D. Bigner, and O. W. Griffith. “Cyclophosphamide resistance in medulloblastoma.Cancer Res 52, no. 19 (October 1, 1992): 5373–78.
Friedman HS, Colvin OM, Kaufmann SH, Ludeman SM, Bullock N, Bigner DD, et al. Cyclophosphamide resistance in medulloblastoma. Cancer Res. 1992 Oct 1;52(19):5373–8.
Friedman, H. S., et al. “Cyclophosphamide resistance in medulloblastoma.Cancer Res, vol. 52, no. 19, Oct. 1992, pp. 5373–78.
Friedman HS, Colvin OM, Kaufmann SH, Ludeman SM, Bullock N, Bigner DD, Griffith OW. Cyclophosphamide resistance in medulloblastoma. Cancer Res. 1992 Oct 1;52(19):5373–5378.

Published In

Cancer Res

ISSN

0008-5472

Publication Date

October 1, 1992

Volume

52

Issue

19

Start / End Page

5373 / 5378

Location

United States

Related Subject Headings

  • gamma-Glutamyltransferase
  • Tumor Cells, Cultured
  • Sensitivity and Specificity
  • Oncology & Carcinogenesis
  • Methionine Sulfoximine
  • Medulloblastoma
  • Male
  • Infant
  • Humans
  • Glutathione Transferase