The broad long-term objective of this study is to define the molecular basis of cisplatin resistance in human ovarian carcinoma cells. This research could be the basis for circumventing and/or exploiting the properties of drug resistant tumors. These findings may have clinical applications. Cells respond to cisplatin by a sequential, time-dependent increase in the genes necessary for repairing cisplatin-induced DNA damage. The oncogene, c-fos, is one of the first genes expressed in response to cisplatin.
The specific aim of this study is to use selective agents to overcome cisplatin resistance, specifically ribozymes that can inhibit oncogene expression. The experimental design will require first the synthesis of a c-fos ribozyme to cleave the c-fos m-RNA and then studies using the pSVO cat plasmid to introduce the ribozyme into cisplatin-resistant ovarian carcinoma cells in tissue culture. The c-fos promoter in the pSVO cat plasmid could activate the c-fos ribozyme in response to cisplatin treatment in human carcinoma cells resistant to cisplatin. The consequence would be to limit the sequential expression of DNA repair genes and render the cells sensitive to cisplatin. Conversely, the c-fos oncogene will be transfected into drug sensitive cells to confirm drug resistance. These studies should test the hypothesis that fos expression may be the first step in a cascade of genes necessary to repair drug induced DNA damage as a mechanism of resistance. If this gene does not contribute to cisplatin resistance, then alternative genes will be tested (i.e. dTMP synthase, DNA polymerase Beta or c-Hras). A wide spectrum of agents can elicit increased c-fos gene expression in cells. Having a probe to selectively inhibit this cascade may offer an enormous insight into not only drug resistance but also to other biological stimuli.
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