• Corpus ID: 19118915

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-hydroperoxycyclophosphamide.

  title={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-hydroperoxycyclophosphamide.},
  author={Christine M. Chresta and Timothy Crook and Robert Leon Souhami},
  journal={Cancer research},
  volume={50 13},
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… 
Glutathione, cell proliferation, and 1,3-bis-(2-chloroethyl)-1-nitrosourea in K562 leukemia.
By destroying GSSG-R and delaying the upregulation of thiol synthesis while escalating GSH utilization and requirements, the nitrosourea created a striking and previously unrecognized window of vulnerability for GSH-dependent processes.
Severe depletion of cellular thiols and glutathione-related enzymes of a carmustine-resistant L1210 strain associates with collateral sensitivity to cyclophosphamide
The severely reduced activity of GST in the L1210/BCNU strain was markedly increased when these cells were made resistant to CPA; the GSSG-R activity, however, remained low, suggesting an irreversible injury of this enzyme by BCNU.
Effect of Combined Treatment with 4-Hydroperoxycyclophosphamide and Fludarabine on Cytotoxicity and Repair of Damaged DNA
A possible role of nucleoside analogs to suppress the repair of damaged DNA as a mechanistic basis for the synergistic cytotoxicity of combined treatment with alkylating agents and nucleosides analogs is suggested.
Cyclophosphamide decreases O6-alkylguanine-DNA alkyltransferase activity in peripheral lymphocytes of patients undergoing bone marrow transplantation.
Observations suggest that a cyclophosphamide-induced decrease in ATase levels in human peripheral lymphocytes in vivo may be due to depletion mediated by the production of intracellular acrolein in patients with advanced Hodgkin's disease.
Detection of single-strand breaks and base damage in DNA of blood cells from leukaemia patients receiving chemo- and radiotherapy.
A sensitive immunochemical method to quantify single-strand breaks (SSB) in the DNA of mammalian cells is developed and applied to study the in vivo induction and repair of DNA damage in WBC of leukaemia patients who prior to BMT were treated with cyclophosphamide and received TBI.
Integrative Gene Expression Profiling Reveals G6PD-Mediated Resistance to RNA-Directed Nucleoside Analogues in B-Cell Neoplasms
It is shown that elevated G6PD expression is necessary to maintain resistance to 8-amino- and 8-chloro-adenosine but insufficient to induce de novo resistance in sensitive cells, and suggests that administration of these agents to patients with B-cell malignancies exhibiting normal levels of G6 PD expression may be particularly efficacious.


Effect of D,L-buthionine-S,R-sulfoximine on cytotoxicity and DNA cross-linking induced by bifunctional DNA-reactive cytostatic drugs in human melanoma cells.
The hypothesis that the potentiation of the cytotoxicity of bifunctional alkylating agents by BSO is due to an increased DNA cross-linking caused by a reduced intracellular conjugation of drug with glutathione, which results in an increased binding of drug to DNA targets is supported.
Inhibition of DNA repair by the 1,3-bis(2-chloroethyl)-1-nitrosourea breakdown product, 2-chloroethyl isocyanate.
It is tentatively suggested that the cytocidal effect of 1,3-bis(2-chloroethyl)-1-nitrosourea may be potentiated by one of its metabolites, 2- chloroethyl isocyanate, through an inhibition of the repair of damaged DNA.
Glutathione depletion as a determinant of sensitivity of human leukemia cells to cyclophosphamide.
The role of glutathione (GSH) as a determinant of cellular sensitivity to the cytotoxic and DNA-damaging effects of cyclophosphamide (CP) was studied in a dual culture system of rat hepatocytes and
Cellular glutathione depletion by diethyl maleate or buthionine sulfoximine: no effect of glutathione depletion on the oxygen enhancement ratio.
It is suggested that GSH depletion by either BSO or DEM sensitizes aerobic cells to radiation but does not appreciably alter the OER.
Carbamoylation of glutathione reductase and changes in cellular and chromosome morphology in a rat cell line resistant to nitrogen mustards but collaterally sensitive to nitrosoureas.
In interphase cells, transmission electron microscopy showed that the most prevalent drug-induced lesions included disappearance of plasma membrane filopodia, appearance of membrane blebbing, and development of irregular crescent-shaped nuclei that correlate with cytotoxic responses of these cell lines to N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea and would be consistent with drug- induced inhibition of glutathione reductase.
Inhibition of the ligase step of excision repair by 2-chloroethyl isocyanate, a decomposition product of 1,3-bis(2-chloroethyl)-1-nitrosourea.
The compound 2-chloroethyl isocyanate, a decomposition product of 1,3-bis(2-chloroethyl)-1-nitrosourea, was studied for its effects on excision repair of DNA in normal human fibroblasts exposed to
Combined effect of buthionine sulfoximine and cyclophosphamide upon murine tumours and bone marrow.
The results suggest a clinical applicability of the combination of BSO and CYC and large ERs were obtained at low CYC doses (high cell survival) and four BSO pre-treatments at an interval of 12 h did not increase the cytotoxicity of CYC to bone marrow stem cells.
Chemosensitization by buthionine sulfoximine in vivo.