Drug resistance to chemotherapeutic agents remains the principal obstacle to improved response rates in cancer patients. Frequently, relapse occurs after chemotherapy; this form of resistance is known as acquired multidrug resistance (MDR); MDR is associated with the expression of an integral membrane protein called P-glycoprotein (P-gp) which is encoded by the multidrug resistance gene, MDR1. P-gp functions as an energy dependent efflux pump which reduces the intracellular concentrations of various cytotoxic drugs by pumping the agents out of the cell. Therefore, disease that is drug resistant is unlikely to be eradicated even by high dose chemotherapy. The approaches to overcome resistance involve, (1) the use of small molecule compounds (MDR reversing agents) which competitively bind to P-gp and are pumped out of the cell by this protein, and (2) P-gp- specific monoclonal antibodies binding to extracellular domains thereby interfering with the function of P-gp. Both approaches have unwanted side effects and their clinical application may prove to be problematic. Innovative approaches and novel model systems that can have an impact upon resistant tumor cells are needed. In the present study, we intend to develop new drugs against the MDR1 gene based on a new proprietary technology known as genetic suppressor elements (GSEs). The GSE approach involves selective inhibition of a specific gene based on antisense oligonucleotides or peptides acting as dominant-negative mutants. The use of this technology will enable us to identify new gene based drugs that will interfere with P-gp expression and/or function, and therefore, sensitize tumor cells to MDR drugs.
This project will result in developing a new class of drugs, genetic suppressor elements' for the reversal of multidrug resistance. These drugs will reverse resistance in MDR tumors resistant to commonly used chemotherapeutic agents.
