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Response to ICRF-159 in cell lines resistant to cleavable complex-forming topoisomerase II inhibitors
S L Davies1, J Bergh, A L Harris
1Imperial Cancer Research Fund Laboratories, University of Oxford, UK.
Abstract:
We have studied the relationship between expression of genes implicated in mediating resistance to cleavable complex-forming topoisomerase II (topo II) inhibitors and cellular sensitivity to ICRF-159, a 'catalytic' inhibitor of topo II. Overexpression of the membrane transporters, P-glycoprotein and multidrug resistance-related protein (MRP), or down-regulation of topo IIalpha and/or -beta, did not confer ICRF-159 resistance. Indeed, marked topo IIalpha down-regulation appeared to be associated with collateral sensitivity to ICRF-159. Our results indicate that the resistance mechanisms that pertain to cleavable complex-forming topo II inhibitors and ICRF-159 are distinct. The evidence presented here suggests that topo IIalpha, not topo IIbeta, is more likely to be the major in vivo target for ICRF-159.
Insights
Cellular sensitivity to ICRF-159, a catalytic topoisomerase II (topo II) inhibitor, was studied. Resistance mechanisms differ from other topo II inhibitors, with topo IIalpha down-regulation potentially increasing sensitivity.
Area of Science:
- Molecular Biology
- Pharmacology
- Cancer Research
Background:
- Topoisomerase II (topo II) inhibitors are crucial in cancer therapy.
- Understanding resistance mechanisms to topo II inhibitors is vital for effective treatment.
- ICRF-159 represents a distinct class of topo II inhibitor, acting catalytically.
Purpose of the Study:
- To investigate the relationship between gene expression related to topo II inhibitor resistance and cellular sensitivity to ICRF-159.
- To determine if known resistance mechanisms, like P-glycoprotein or MRP overexpression, affect ICRF-159 sensitivity.
- To elucidate the specific topo II isoforms involved in cellular response to ICRF-159.
Main Methods:
- Studying the expression of genes involved in resistance to cleavable complex-forming topo II inhibitors.
- Assessing cellular sensitivity to ICRF-159 in relation to these gene expression changes.
- Analyzing the impact of P-glycoprotein and multidrug resistance-related protein (MRP) expression.
- Evaluating the role of topo IIalpha and topo IIbeta down-regulation.
Main Results:
- Overexpression of P-glycoprotein or MRP did not lead to ICRF-159 resistance.
- Down-regulation of topo IIalpha or topo IIbeta did not confer resistance.
- Marked down-regulation of topo IIalpha was associated with collateral sensitivity to ICRF-159.
- Resistance mechanisms for cleavable complex-forming topo II inhibitors and ICRF-159 are distinct.
Conclusions:
- The mechanisms conferring resistance to cleavable complex-forming topoisomerase II (topo II) inhibitors are different from those affecting sensitivity to the catalytic inhibitor ICRF-159.
- Topo IIalpha appears to be the primary in vivo target of ICRF-159, rather than topo IIbeta.
- Down-regulation of topo IIalpha may lead to collateral sensitivity, suggesting novel therapeutic strategies.