Skip to main content

Elevated DNA polymerase alpha, DNA polymerase beta, and DNA topoisomerase II in a melphalan-resistant rhabdomyosarcoma xenograft that is cross-resistant to nitrosoureas and topotecan.

Publication ,  Journal Article
Friedman, HS; Dolan, ME; Kaufmann, SH; Colvin, OM; Griffith, OW; Moschel, RC; Schold, SC; Bigner, DD; Ali-Osman, F
Published in: Cancer Res
July 1, 1994

Previous investigations have revealed that the human TE-671 MR human rhabdomyosarcoma xenograft selected in vivo for melphalan resistance (M. C. Rosenberg, et al., Cancer Res., 49: 6917-6922, 1989) is cross-resistant to a wide variety of alkylating agents and to bleomycin, but is collaterally sensitive to etoposide. Although glutathione levels were noted to be elevated in TE-671 MR compared to the melphalan-sensitive parental TE-671 xenograft, treatment with buthionine sulfoximine to deplete glutathione levels did not fully restore melphalan sensitivity in the TE-671 MR xenograft. The present studies were undertaken to search for additional mechanisms of resistance in the TE-671 MR xenograft. Drug sensitivity testing performed at the dose of agents that was lethal to 10% of the animals revealed that the TE-671 MR xenograft maintained resistance to the bifunctional cross-linking agent 1,3-bis(2-chloroethyl)-1-nitrosourea and was cross-resistant to the topoisomerase I poison topotecan. Treatment with buthionine sulfoximine did not sensitize the TE-671 MR xenograft to 1,3-bis(2-chloroethyl)-1-nitrosourea. Further, even though O6-alkylguanine-DNA alkyltransferase levels were high in both the TE-671 and TE-671 MR xenografts, depletion of O6-alkylguanine-DNA alkyltransferase activity by treatment with O6-benzylguanine substantially sensitized the TE-671 xenografts but not the TE-671 MR xenografts, suggesting an additional mechanism of resistance. Measurement of additional enzyme activities that might be involved in DNA repair revealed significant elevations in DNA polymerase alpha (46 +/- 8 (SD) units/mg protein in TE-671, 69 +/- 6 units/mg protein in TE-671 MR, P < 0.05) and DNA polymerase beta (0.43 +/- 0.01 units/mg protein in TE-671, 0.78 +/- 0.12 units/mg protein in TE-671 MR, P < 0.05) but not DNA polymerase delta or total DNA ligase. Examination of topoisomerases by activity assays and Western blotting revealed a 2-fold increase in topoisomerase II and a 2-fold decrease in topoisomerase I in the TE-671 MR xenograft compared to the parental xenograft, apparently explaining the collateral sensitivity to etoposide and cross-resistance to topotecan. These results suggest that TE-671 MR xenografts contain multiple changes in activities of DNA repair-related proteins and other nuclear proteins that could contribute to alkylating agent resistance.

Duke Scholars

Published In

Cancer Res

ISSN

0008-5472

Publication Date

July 1, 1994

Volume

54

Issue

13

Start / End Page

3487 / 3493

Location

United States

Related Subject Headings

  • Transplantation, Heterologous
  • Transferases
  • Topotecan
  • Rhabdomyosarcoma
  • Oncology & Carcinogenesis
  • Mice, Nude
  • Mice, Inbred BALB C
  • Mice
  • Melphalan
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Friedman, H. S., Dolan, M. E., Kaufmann, S. H., Colvin, O. M., Griffith, O. W., Moschel, R. C., … Ali-Osman, F. (1994). Elevated DNA polymerase alpha, DNA polymerase beta, and DNA topoisomerase II in a melphalan-resistant rhabdomyosarcoma xenograft that is cross-resistant to nitrosoureas and topotecan. Cancer Res, 54(13), 3487–3493.
Friedman, H. S., M. E. Dolan, S. H. Kaufmann, O. M. Colvin, O. W. Griffith, R. C. Moschel, S. C. Schold, D. D. Bigner, and F. Ali-Osman. “Elevated DNA polymerase alpha, DNA polymerase beta, and DNA topoisomerase II in a melphalan-resistant rhabdomyosarcoma xenograft that is cross-resistant to nitrosoureas and topotecan.Cancer Res 54, no. 13 (July 1, 1994): 3487–93.
Friedman HS, Dolan ME, Kaufmann SH, Colvin OM, Griffith OW, Moschel RC, Schold SC, Bigner DD, Ali-Osman F. Elevated DNA polymerase alpha, DNA polymerase beta, and DNA topoisomerase II in a melphalan-resistant rhabdomyosarcoma xenograft that is cross-resistant to nitrosoureas and topotecan. Cancer Res. 1994 Jul 1;54(13):3487–3493.

Published In

Cancer Res

ISSN

0008-5472

Publication Date

July 1, 1994

Volume

54

Issue

13

Start / End Page

3487 / 3493

Location

United States

Related Subject Headings

  • Transplantation, Heterologous
  • Transferases
  • Topotecan
  • Rhabdomyosarcoma
  • Oncology & Carcinogenesis
  • Mice, Nude
  • Mice, Inbred BALB C
  • Mice
  • Melphalan
  • Male