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Melphalan transport, glutathione levels, and glutathione-S-transferase activity in human medulloblastoma.

Publication ,  Journal Article
Friedman, HS; Skapek, SX; Colvin, OM; Elion, GB; Blum, MR; Savina, PM; Hilton, J; Schold, SC; Kurtzberg, J; Bigner, DD
Published in: Cancer Res
October 1, 1988

Melphalan transport, glutathione levels, and glutathione-S-transferase activity were measured in two continuous human medulloblastoma cell lines and transplantable xenografts in athymic nude mice, TE-671 and Daoy. In vitro mean glutathione levels were 10.06 nmol/10(6) cells in TE-671 and 2.96 nmol/10(6) cells in Daoy. In vitro mean glutathione-S-transferase values were 91.52 nmol/min/mg protein in TE-671 and 50.31 nmol/min/mg protein in Daoy. Transport studies revealed kinetic parameters of Km = 108.3 microM, Vmax = 363.1 pmol/10(6) cells/min in TE-671 and Km = 111.7 microM, Vmax = 180.6 pmol/10(6) cells/min in Daoy. Melphalan transport was inhibited by both DL-alpha-2-aminobicyclo[2.2.1]heptane-2- carboxylic acid and sodium ion depletion in TE-671 and Daoy cells in vitro, indicating that both systems of amino acid transport are functional in these medulloblastoma lines. In vivo s.c. xenograft glutathione values were lower (7.79 nmol/mg protein) in TE-671 than in Daoy (13.68 nmol/mg protein). The mean plasma concentration in mice given a 10% lethal dose (71.3 mg/m2) of melphalan i.p. was 50.3 microM at 10 min, with the half-life of 29.9 min. At this dose, s.c. xenograft levels were 2- to 3-fold higher in TE-671 than in Daoy tumors for the 3-h period measured. These studies demonstrate transport parameters confirming facilitated transport of melphalan in human medulloblastoma, a mean murine plasma melphalan concentration (following treatment with melphalan) above the in vitro drug dose at which there is a 90% reduction in the number of colonies in comparison to controls for TE-671 and Daoy for 2 h, and glutathione and glutathione-S-transferase levels in the same range previously reported in other melphalan-sensitive and melphalan-resistant human tumors. Future work with spontaneous and acquired melphalan-resistant human medulloblastoma cell lines and xenografts will define the role of these mechanisms in mediating drug resistance.

Duke Scholars

Published In

Cancer Res

ISSN

0008-5472

Publication Date

October 1, 1988

Volume

48

Issue

19

Start / End Page

5397 / 5402

Location

United States

Related Subject Headings

  • Time Factors
  • Sodium
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation
  • Mice
  • Melphalan
  • Medulloblastoma
  • Kinetics
  • Humans
  • Glutathione Transferase
 

Citation

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Friedman, H. S., Skapek, S. X., Colvin, O. M., Elion, G. B., Blum, M. R., Savina, P. M., … Bigner, D. D. (1988). Melphalan transport, glutathione levels, and glutathione-S-transferase activity in human medulloblastoma. Cancer Res, 48(19), 5397–5402.
Friedman, H. S., S. X. Skapek, O. M. Colvin, G. B. Elion, M. R. Blum, P. M. Savina, J. Hilton, S. C. Schold, J. Kurtzberg, and D. D. Bigner. “Melphalan transport, glutathione levels, and glutathione-S-transferase activity in human medulloblastoma.Cancer Res 48, no. 19 (October 1, 1988): 5397–5402.
Friedman HS, Skapek SX, Colvin OM, Elion GB, Blum MR, Savina PM, et al. Melphalan transport, glutathione levels, and glutathione-S-transferase activity in human medulloblastoma. Cancer Res. 1988 Oct 1;48(19):5397–402.
Friedman, H. S., et al. “Melphalan transport, glutathione levels, and glutathione-S-transferase activity in human medulloblastoma.Cancer Res, vol. 48, no. 19, Oct. 1988, pp. 5397–402.
Friedman HS, Skapek SX, Colvin OM, Elion GB, Blum MR, Savina PM, Hilton J, Schold SC, Kurtzberg J, Bigner DD. Melphalan transport, glutathione levels, and glutathione-S-transferase activity in human medulloblastoma. Cancer Res. 1988 Oct 1;48(19):5397–5402.

Published In

Cancer Res

ISSN

0008-5472

Publication Date

October 1, 1988

Volume

48

Issue

19

Start / End Page

5397 / 5402

Location

United States

Related Subject Headings

  • Time Factors
  • Sodium
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation
  • Mice
  • Melphalan
  • Medulloblastoma
  • Kinetics
  • Humans
  • Glutathione Transferase