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Abstract

The effects of suppressing c-fos oncogene expression on drug or radiation resistant mammalian cells are described. A2780S human ovarian carcinoma cells with resistance to actinomycin D were isolated and the resultant A2780AD 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 expression of c-fos, followed by that of mdr-1, c-jun, and p53. Reversal of the MDR phenotype by the anti-mdr ribozyme occurred one-fourth as rapidly as that induced by the anti-fos ribozyme. These studies demonstrate the primacy of the c-fos oncogene in maintaining the resistant phenotype in human cancer cells. Thus, down regulation of fos/jun will make resistant cancer cells more sensitive to conventional treatment, i.e., cancer chemotherapeutic agents and/or radiation.

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First Claim