Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 38, Issue 4, pp 349–354 | Cite as

Enhancement of melphalan activity by inhibition of DNA polymerase-α and DNA polymerase-β

  • K. Moynihan
  • Gertrude B. Elion
  • Francis Ali-Osman
  • S. Marcelli
  • S. Keir
  • Darell D. Bigner
  • H. S. Friedman
ORIGINAL ARTICLE

Abstract

Our previous studies exploring melphalan resistance in the human rhabdomyosarcoma xenograft TE-671 MR revealed elevation of DNA polymerase-α and DNA polymerase-β . 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-α was inhibited using aphidicolin glycinate (AG) and DNA polymerase-β 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-α to 80% and 72% of control in TE-671 and 64% and 37% in TE-671 MR, and DDC inhibited DNA polymerase-β 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.

Key words Melphalan Drug resistance Antineoplastic agents DNA polymerases Neoplasm transplantation 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • K. Moynihan
    • 1
  • Gertrude B. Elion
    • 2
  • Francis Ali-Osman
    • 4
  • S. Marcelli
    • 1
  • S. Keir
    • 1
  • Darell D. Bigner
    • 3
  • H. S. Friedman
    • 1
  1. 1.Department of Pediatrics, Duke University Medical Center, Durham, NC 27710 USAUS
  2. 2.Department of Pharmacology, Duke University Medical Center, Durham, NC 27710 USAUS
  3. 3.Department of Pathology, Duke University Medical Center, Durham, NC 27710 USAUS
  4. 4.Department of Experimental Pediatrics, M.D. Anderson Cancer Center, Houston, TX 77030, USAUS

Personalised recommendations