RIBOZYME-MEDIATED REVERSAL OF THE MULTIDRUG-RESISTANT PHENOTYPE

This study examined the effects of suppressing c-fos oncogene expressi on on multidrug resistance (MDR). A2780S human ovarian carcinoma cells with resistance to actinomycin D were isolated and the resultant A278 0AD cells exhibited the MDR phenotype. A hammerhead ribozyme designed to cleave fos RNA cloned into the pMAMneo plasmid was transfected into A2780AD cells. Induction of the ribozyme resulted in decreased expres sion of c-fos, as well. as that of the MDR gene (mdr-1), c-jun, and mu tant p53. The transformants displayed altered morphology and restored sensitivity to chemotherapeutic agents comprising the MDR phenotype. A n anti-mdr ribozyme separately expressed in A2780AD cells efficiently degraded mdr-1 mRNA. However, reversal of the MDR phenotype by the ant i-mdr ribozyme occurred one-fourth as rapidly as that induced by the a nti fos ribozyme. These results reinforce the central role played by c -fos in drug resistance through its participation in signal transducti on pathways.