Cancer Chemotherapy and Pharmacology

, Volume 40, Issue 5, pp 409–414 | Cite as

Characterization of the mechanisms of busulfan resistance in a human glioblastoma multiforme xenograft

  • C. Bradley Hare
  • Gertrude B. Elion
  • O. Michael Colvin
  • Francis Ali-Osman
  • Owen W. Griffith
  • William P. Petros
  • Stephen Keir
  • Susan L. Marcelli
  • Darell D. Bigner
  • Henry S. Friedman
ORIGINAL ARTICLE

Abstract

Busulfan is an alkylating agent commonly used in the treatment of chronic myelogenous leukemia and in combination with cyclophosphamide in preparation for allogeneic bone marrow transplantation. Serial treatment of a childhood high-grade glioma xenograft (D-456 MG) with busulfan resulted in a busulfan-resistant xenograft, D-456 MG(BR). Cross-resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea was seen but not resistance to cyclophosphamide or CPT-11. Cytoplasmic levels of glutathione in D-456 MG(BR) were approximately one-half those found in D-456 MG. This depletion could not be explained by levels of glutathione-S-transferase, or by amplification, rearrangement, or increased levels of transcript of γ-glutamylcysteine synthetase. Furthermore, depletion of glutathione in D-456 MG did not alter busulfan activity. Quantitation of busulfan levels in D-456 MG and D-456 MG(BR) xenografts following treatment of mice at the dose lethal to 10% of the animals demonstrated that significantly lower levels of drug were achieved in D-456 MG(BR). These studies suggest that alterations in drug transport or metabolism of busulfan may play a role in the resistance of D-456 MG(BR) to this alkylator.

Key words Busulfan Glioblastoma multiforme Xenograft Drug resistance 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1997

Authors and Affiliations

  • C. Bradley Hare
    • 1
  • Gertrude B. Elion
    • 2
  • O. Michael Colvin
    • 3
  • Francis Ali-Osman
    • 5
  • Owen W. Griffith
    • 6
  • William P. Petros
    • 3
  • Stephen Keir
    • 1
  • Susan L. Marcelli
    • 1
  • Darell D. Bigner
    • 4
  • Henry S. Friedman
    • 1
  1. 1.Department of Pediatrics, Duke University Medical Center, Box 3624, Durham, NC 27710, USA Tel. 919-684-8722; Fax 919-684-9818; E-mail fried003@duke.mc.eduUS
  2. 2.Department of Pharmacology, Duke University Medical Center, Durham, NC 27710, USAUS
  3. 3.Department of Medicine, Duke University Medical Center, Durham, NC 27710, USAUS
  4. 4.Department of Pathology, Duke University Medical Center, Durham, NC 27710, USAUS
  5. 5.Department of Experimental Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USAUS
  6. 6.Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USAUS

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