Multiple drug resistance (MDR) is the major cause for chemotherapeutic failure in many cancer patients. Large ribonucleoprotein complexes, termed vaults, appear to mediate MDR in a number of tumor types. Vault function will be examined by targeting various oligomers, including peptide nucleic acids (PNA), locked nucleic acids (LNA) and small interfering RNAs (siRNA), to two of its functional components, MVP and vRNA. This project will be initiated by designing and obtaining oligomers targeted to both MVP mRNA and vRNA. PNAs, LNAs and siRNAs have already been successfully transfected into a non-small cell lung cancer line, SW1573 and its MDR subline SW1573/2R120. Preliminary studies have produced a siRNA that is able to reduce MVP expression more than 90 percent. Ultimately, oligomers will be introduced into chemosensitive and drug resistant cells and then screened for their effectiveness in disrupting vault mediated drug efflux in MDR cells. The successful identification and intracellular delivery of vault inhibitory oligomers may provide therapeutic lead compounds for cancers previously unresponsive to standard treatment protocols.
