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Genetic Suppressor Elements Proving Useful in Drug Resistance Research

Genetic Suppressor Elements Proving Useful in Drug Resistance Research

SEATTLE--Researchers at the University of Illinois at Chicago are using novel approaches to identify and analyze the genes involved in making cancer cells more resistant, or more sensitive, to chemotherapy agents, Igor Roninson, PhD, head of the Molecular Oncology Division, said at a symposium held in conjunction with the American Society of Hematology annual meeting.

Inhibitors of several signal transduction pathways can prevent induction of the multidrug-resistance gene (MDR-1) in drug-treated cells, Dr. Roninson said, and MDR-1 is only one of many genes involved in determining the cellular response to chemotherapeutic treatment.

His laboratory has developed a new approach to the analysis of these genes, using genetic suppressor elements (GSEs). GSEs are short gene fragments that counteract the gene from which they are derived, by encoding dominant negative peptides or efficient antisense RNAs.

GSEs can be isolated from recombinant retroviral libraries by looking for improved survival or enhanced cell death in transduced cells exposed to a particular drug. This allows the team to analyze the specific mechanisms of resistance.

Another advantage of this approach is that it can uncover clinically relevant resistance mechanisms that do not occur in drug-resistant cell lines, because these lines have been artificially selected by gradually increasing drug levels.

Since GSEs can potentially inactivate particular genes or their protein products, they may prove useful as chemosen-sitizing agents. By introducing a GSE for the BCL2 apoptosis suppressor into leukemia and breast cancer cell lines, Dr. Roninson increased sensitivity to chemo-therapy by a full order of magnitude.

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