Genetic Suppressor Elements Proving Useful in Drug Resistance Research

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

Inhibitors of several signal transduction pathways can preventinduction of the multidrug-resistance gene (MDR-1) in drug-treatedcells, Dr. Roninson said, and MDR-1 is only one of many genesinvolved in determining the cellular response to chemotherapeutictreatment.

His laboratory has developed a new approach to the analysis ofthese genes, using genetic suppressor elements (GSEs). GSEs areshort gene fragments that counteract the gene from which theyare derived, by encoding dominant negative peptides or efficientantisense RNAs.

GSEs can be isolated from recombinant retroviral libraries bylooking for improved survival or enhanced cell death in transducedcells exposed to a particular drug. This allows the team to analyzethe specific mechanisms of resistance.

Another advantage of this approach is that it can uncover clinicallyrelevant resistance mechanisms that do not occur in drug-resistantcell lines, because these lines have been artificially selectedby gradually increasing drug levels.

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