Characterization of the mechanisms of busulfan resistance in a human glioblastoma multiforme xenograft.
Journal Article (Journal Article)
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 gamma-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.
Full Text
Duke Authors
Cited Authors
- Hare, CB; Elion, GB; Colvin, OM; Ali-Osman, F; Griffith, OW; Petros, WP; Keir, S; Marcelli, SL; Bigner, DD; Friedman, HS
Published Date
- 1997
Published In
Volume / Issue
- 40 / 5
Start / End Page
- 409 - 414
PubMed ID
- 9272117
International Standard Serial Number (ISSN)
- 0344-5704
Digital Object Identifier (DOI)
- 10.1007/s002800050678
Language
- eng
Conference Location
- Germany