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Cross-resistance patterns in ACNU-resistant glioma sublines in culture
1Department of Neurosurgery, Hiroshima University School of Medicine, Japan.
Abstract:
Three ACNU-resistant clones (R1, R3, and R12) were isolated from 9L rat glioma cells under selection pressure of ACNU in vitro. The authors have investigated the mechanisms of resistance and characteristics of these clones at the cellular level by studying cross-resistance patterns to chemical and physical agents. Although these resistant sublines showed complete cross-resistance to methyl-chloroethylnitrosourea (MCNU), no cross-resistance was observed for other alkylating agents, while each of the resistant sublines showed partial cross-resistance to structurally dissimilar toxic agents (vinblastine, Adriamycin, and VP-16). No difference in ACNU uptake was observed between 9L and R3 cells, and resistance patterns among alkylating agents suggested that the mechanism of ACNU resistance was specific to bifunctional nitrosoureas. Based on a transport study, this multidrug resistance could be explained by reduced intracellular uptake of these drugs, but there seemed little possibility that membrane P-glycoprotein, which usually is observed in typical multidrug-resistant cells, was expressed in these ACNU-resistant cells because enhanced drug efflux was not found in ACNU-resistant sublines. Significant collateral sensitivity to L-asparaginase indicated that ACNU might disturb the asparagine synthetic pathways by its mutagenic action. The increased level of total glutathione in the resistant sublines may be one mechanism of radiation or ACNU resistance.
Insights
ACNU-resistant rat glioma cells exhibit cross-resistance to similar agents but not other alkylating drugs. Resistance may involve reduced drug uptake and increased glutathione, not P-glycoprotein.
Area of Science:
- Neuro-oncology
- Cancer Pharmacology
- Cellular Biology
Background:
- ACNU (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea) is a chemotherapy agent used for brain tumors.
- Understanding drug resistance mechanisms is crucial for improving cancer treatment efficacy.
Purpose of the Study:
- To investigate the cellular mechanisms of ACNU resistance in rat glioma cells.
- To characterize cross-resistance patterns to various cytotoxic agents in ACNU-resistant clones.
Main Methods:
- Isolation of ACNU-resistant 9L rat glioma clones (R1, R3, R12) through in vitro selection.
- Assessment of cross-resistance patterns to alkylating agents, cytotoxic drugs, and radiation.
- Measurement of ACNU uptake and analysis of P-glycoprotein expression.
- Evaluation of glutathione levels and collateral sensitivity to L-asparaginase.
Main Results:
- ACNU-resistant clones showed complete cross-resistance to MCNU but not other alkylating agents.
- Partial cross-resistance was observed for structurally dissimilar agents like vinblastine, Adriamycin, and VP-16.
- No difference in ACNU uptake was detected; resistance mechanism appears specific to bifunctional nitrosoureas.
- Reduced intracellular drug uptake, not P-glycoprotein efflux, likely contributes to multidrug resistance.
- Collateral sensitivity to L-asparaginase suggests ACNU may affect asparagine synthesis.
- Increased total glutathione levels in resistant sublines may contribute to ACNU or radiation resistance.
Conclusions:
- ACNU resistance in 9L rat glioma cells is specific to bifunctional nitrosoureas and may involve reduced drug uptake and elevated glutathione.
- The absence of P-glycoprotein suggests a unique multidrug resistance mechanism.
- Further research into glutathione's role and ACNU's impact on metabolic pathways is warranted for therapeutic strategies.