Reversal of Multidrug Resistance--A Novel Approach

Drug resistance to chemotherapeutic agents remains the principal obstacle to improved response ratepatients. Frequently, relapse occurs after chemotherapy; this form of resistance is known as acquire(MDR). MDR is associated with the expression of an integral membrane protein called P-glycoprotein (encoded by the multidrug resistance gene, MDR1. P-gp functions as an energy dependent efflux pump whintracellular concentrations of various cytotoxic drugs by pumping the agents out of the cell. Thereresistant is unlikely to be eradicated even by high dose chemotherapy. The approaches to overcome rethe use of small molecule compounds (MDR reversing agents) which competitively bind to P-gp and arecell by this protein, and (2) P-gp- specific monoclonal antibodies binding to extracellular domainsthe function of P-gp. Both approaches have unwanted side effects and their clinical application mayproblematic. Innovative approaches and novel model systemss that can have an impact upon resistant tneeded. In the present study, we intend to develop new drugs against the MDR1 gene based on a new prtechnology known as genetic suppressor elements (GSEs). The GSE approach involves selective inhibitigene based on antisense oligonucleotides or peptides acting as dominant-negative mutants. The use ofenable us to identify new gene based drugs that will interfere with P-gp expression and/or function,tumor cells to MDR drugs.