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Enhancement of melphalan activity by inhibition of DNA polymerase-alpha and DNA polymerase-beta.

Publication ,  Journal Article
Moynihan, K; Elion, GB; Ali-Osman, F; Marcelli, S; Keir, S; Bigner, DD; Friedman, HS
Published in: Cancer Chemother Pharmacol
1996

Our previous studies exploring melphalan resistance in the human rhabdomyosarcoma xenograft TE-671 MR revealed elevation of DNA polymerase-alpha and DNA polymerase-beta. The present study evaluated the alteration of melphalan activity in TE-671 (melphalan-sensitive) and TE-671 MR (melphalan-resistant) subcutaneous xenografts in nude mice after DNA polymerase-alpha was inhibited using aphidicolin glycinate (AG) and DNA polymerase-beta was inhibited using dideoxycytidine (DDC). Administration of AG or DDC did not produce toxicity or demonstrate antineoplastic activity when given alone. AG (90 mg/m2) enhanced the activity of melphalan against TE-671, with growth delays increasing by 8.4, 15.8, and 21.2 days over the regimen with melphalan only. AG (180 mg/m2) only modestly increased melphalan activity against TE-671 MR, with the growth delays increasing from 9.6 and 12.1 days using melphalan alone to 12.1 and 14.5 days using melphalan plus AG. AG (180 mg/m2) plus melphalan (the dose lethal to 10% of animals) produced greater weight loss compared with melphalan alone, whereas DDC plus melphalan produced no additional toxicity. DDC modestly enhanced the activity of melphalan plus AG against TE-671 MR. AG plus O6-benzylguanine did not increase the activity of 1,3-bis(2-chloroethyl)-1-nitrosourea against TE-671 or TE-671 MR. AG (90 mg/m2 and 180 mg/m2) inhibited DNA polymerase-alpha to 80% and 72% of control in TE-671 and 64% and 37% in TE-671 MR, and DDC inhibited DNA polymerase-beta to 59% in TE-671 and 48% in TE-671 MR. These results suggest a role for AG-mediated enhancement of melphalan activity, particularly in the treatment of newly diagnosed, melphalan-sensitive tumors.

Duke Scholars

Published In

Cancer Chemother Pharmacol

DOI

ISSN

0344-5704

Publication Date

1996

Volume

38

Issue

4

Start / End Page

349 / 354

Location

Germany

Related Subject Headings

  • Zalcitabine
  • Rhabdomyosarcoma
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation
  • Mice, Nude
  • Mice, Inbred BALB C
  • Mice
  • Melphalan
  • Male
  • Humans
 

Citation

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Moynihan, K., Elion, G. B., Ali-Osman, F., Marcelli, S., Keir, S., Bigner, D. D., & Friedman, H. S. (1996). Enhancement of melphalan activity by inhibition of DNA polymerase-alpha and DNA polymerase-beta. Cancer Chemother Pharmacol, 38(4), 349–354. https://doi.org/10.1007/s002800050494
Moynihan, K., G. B. Elion, F. Ali-Osman, S. Marcelli, S. Keir, D. D. Bigner, and H. S. Friedman. “Enhancement of melphalan activity by inhibition of DNA polymerase-alpha and DNA polymerase-beta.Cancer Chemother Pharmacol 38, no. 4 (1996): 349–54. https://doi.org/10.1007/s002800050494.
Moynihan K, Elion GB, Ali-Osman F, Marcelli S, Keir S, Bigner DD, et al. Enhancement of melphalan activity by inhibition of DNA polymerase-alpha and DNA polymerase-beta. Cancer Chemother Pharmacol. 1996;38(4):349–54.
Moynihan, K., et al. “Enhancement of melphalan activity by inhibition of DNA polymerase-alpha and DNA polymerase-beta.Cancer Chemother Pharmacol, vol. 38, no. 4, 1996, pp. 349–54. Pubmed, doi:10.1007/s002800050494.
Moynihan K, Elion GB, Ali-Osman F, Marcelli S, Keir S, Bigner DD, Friedman HS. Enhancement of melphalan activity by inhibition of DNA polymerase-alpha and DNA polymerase-beta. Cancer Chemother Pharmacol. 1996;38(4):349–354.
Journal cover image

Published In

Cancer Chemother Pharmacol

DOI

ISSN

0344-5704

Publication Date

1996

Volume

38

Issue

4

Start / End Page

349 / 354

Location

Germany

Related Subject Headings

  • Zalcitabine
  • Rhabdomyosarcoma
  • Oncology & Carcinogenesis
  • Neoplasm Transplantation
  • Mice, Nude
  • Mice, Inbred BALB C
  • Mice
  • Melphalan
  • Male
  • Humans