COTRANSFECTION OF MDR1 AND MRP ANTISENSE RNAS ABOLISHES THE DRUG-RESISTANCE IN MULTIDRUG-RESISTANT HUMAN LUNG-CANCER CELLS

The resistance of lung cancer cells to the therapeutic actions of anti cancer drugs is a serious clinical problem often encountered during ca ncer chemotherapy. It is very important, therefore, to investigate how to prevent and/or reverse this drug resistance. To this end, we took advantage of the fact that the overexpression of MDR1 and MRP genes, t wo genes known to be associated with the development of drug resistanc e, is very common in lung cancer. We used antisense RNA in an attempt to prevent expression of the protein products of these genes. Using a retrovirus, we introduced the antisense RNAs of MDR1 and MRP genes int o doxorubicin-selected, multidrug-resistant GAOK cells, a cell which o verexpresses both MDR1 and MRP genes. The expression levels of the pro ducts of the MDR1 gene (Pgp) and MRP gene (Mrp) in the transfected cel ls were analyzed using flow cytometry, and the drug resistances of the transfected cells were detected by a cell viability (MTT) assay. The expression of Pgp and Mrp in the transfected cells was almost complete ly inhibited by the antisense RNAs: expression levels decreased 64% an d 93%, respectively. In parallel, the drug resistance of these cells d ecreased about 99% to doxorubicin, 98% to vinblastine, and 97% to colc hicine. These results show that: a) antisense RNAs can attenuate drug resistance an inhibition that might lead to new treatments for patient s who are, or become, refractory to conventional chemotherapy; b) MDR1 and MRP appeal to be cooperating to confer drug resistance in GAOK ce lls.