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
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
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.