The development of drug resistance represents a major limitation of presently employed chemotherapeutic agents. In this regard, diverse mechanisms have been shown to be etiologic of the drug resistant phenotype. In many instances, the specific molecular basis of drug resistance has been defined. Mutational changes that lead to the drug resistant phenotype include modifications in the structure or level of topoisemerase, increased detoxification reactions, interference with delivery of cytotoxic drugs to intracellular targets,or overexpression of selected growth factor receptors. In addition, alterations affecting the regulation of the cell cycle and apoptosis are highly associated with drug resistance. Thus, based upon an understanding of the molecular basis ofdrug resistance, strategies may be proposed to correct the genetic lesions etiologic of the drug resistant phenotype. To this end, we have developed a novel method to achieve targeted oncoprotein ablation based on intracellular expression of a single-chain antibody. We have shown that this method can accomplish phenotypic alterations in tumor cells based upon downregulationof the target oncoprotein. In addition, we have demonstrated that the technique of anti-oncogene sFv-mediated knockout can enhance tumor cell chemosensitivity. It is thus our hypothesis that the sFv-mediated knockout technique can be developed as a means to achieve enhanced chemosensitization as a therapeutic modality for ovarian neoplasms of epithelial origin. In this proposal, we will thus determine the parameters that modulate chemosensitivity induced by intracellular expression of an anti-erbB-2 sFv. In addition, we will evaluate single chain antibodies targeting other gene products relevant to the pathogenesis of ovarian carcinoma and to explore their utility in accomplishing tumor cell chemosensitization in animal models relevant to human carcinoma of the ovary. It is evident that novel therapeutic modalities are needed for the successful treatment of epithelial ovarian carcinoma. We have demonstrated that sFv-mediated modulation of target oncogene products may allow enhanced sensitivity to chemotherapeutic agents. It is anticipated that the experiments described herein will allow the definition of th eoptimal biologic parameters relevant to implementation of this strategy. These studies would thus establish the basis for the development of a human clinicalprotocol for epithelial ovarian carcinoma based upon this novel approach.
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