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

被引:0
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作者
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
机构
[1] Department of Pediatrics,
[2] Duke University Medical Center,undefined
[3] Box 3624,undefined
[4] Durham,undefined
[5] NC 27710,undefined
[6] USA Tel. 919-684-8722; Fax 919-684-9818; E-mail fried003@duke.mc.edu,undefined
[7] Department of Pharmacology,undefined
[8] Duke University Medical Center,undefined
[9] Durham,undefined
[10] NC 27710,undefined
[11] USA,undefined
[12] Department of Medicine,undefined
[13] Duke University Medical Center,undefined
[14] Durham,undefined
[15] NC 27710,undefined
[16] USA,undefined
[17] Department of Pathology,undefined
[18] Duke University Medical Center,undefined
[19] Durham,undefined
[20] NC 27710,undefined
[21] USA,undefined
[22] Department of Experimental Pediatrics,undefined
[23] University of Texas,undefined
[24] MD Anderson Cancer Center,undefined
[25] Houston,undefined
[26] TX 77030,undefined
[27] USA,undefined
[28] Department of Biochemistry,undefined
[29] Medical College of Wisconsin,undefined
[30] Milwaukee,undefined
[31] WI 53226,undefined
[32] USA,undefined
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Key words Busulfan; Glioblastoma multiforme; Xenograft; Drug resistance;
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摘要
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.
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页码:409 / 414
页数:5
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