title: Characterization of the mechanisms of busulfan resistance in a human glioblastoma multiforme xenograft.
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 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.
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: C B
authors.initials: CB
authors.lastname: Hare
authors.forename: G B
authors.initials: GB
authors.lastname: Elion
authors.forename: O M
authors.initials: OM
authors.lastname: Colvin
authors.forename: F
authors.initials: F
authors.lastname: Ali-Osman
authors.forename: O W
authors.initials: OW
authors.lastname: Griffith
authors.forename: W P
authors.initials: WP
authors.lastname: Petros
authors.forename: S
authors.initials: S
authors.lastname: Keir
authors.forename: S L
authors.initials: SL
authors.lastname: Marcelli
authors.forename: D D
authors.initials: DD
authors.lastname: Bigner
authors.forename: H S
authors.initials: HS
authors.lastname: Friedman
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000493:pharmacokinetics*; D015139:Blotting, Southern; D002066:Busulfan / Q000378:metabolism / Q000493:pharmacokinetics*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005909:Glioblastoma / Q000201:enzymology / Q000378:metabolism*; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014183:Transplantation, Heterologous
chemical_list: D018906:Antineoplastic Agents, Alkylating; D005721:Glutamate-Cysteine Ligase; D002066:Busulfan