Depletion of cellular glutathione by N,N'-Bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea as a determinant of sensitivity of K562 human leukemia cells to 4-hydroperoxycyclo-phosphamide

N,N'-Bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea (BHCNU) is a nitrosourea which has carbamoylating but not alkylating activity. It has been shown to carbamoylate and inactivate glutathione reductase thereby reducing the intracellular levels of glutathione (GSH). Since GSH depletion by bu...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1990-01, Vol.50 (13), p.4067-4071
Main Authors: Chresta, C M, Crook, T R, Souhami, R L
Format: Article
Language:English
Subjects:
4-hydroperoxycyclophosphamide
glutathione
nitrosourea
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Summary:N,N'-Bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea (BHCNU) is a nitrosourea which has carbamoylating but not alkylating activity. It has been shown to carbamoylate and inactivate glutathione reductase thereby reducing the intracellular levels of glutathione (GSH). Since GSH depletion by buthionine-S,R-sulfoximine potentiates the cytotoxicity of cyclophosphamide, with a corresponding increase in DNA cross-linking, we have investigated the potential interaction between BHCNU and cyclophosphamide. These findings demonstrate that BHCNU potentiates the cytotoxicity of 4-hydroperoxycyclo phosphamide and suggest that this is due to the increased formation of DNA interstrand cross-links caused by a reduced intracellular conjugation of 4-hydroperoxycyclo-phosphamide with glutathione which results in an increased binding of 4-hydroperoxycyclo phosphamide to DNA targets.
ISSN:0008-5472