Underlying any future chemotherapeutic advances in the treatment of malignant gliomas will be a further understanding of the intracellular mechanisms of growth regulation. Recent work suggests that the Protein Kinase C (PKC) signal transduction system may function as a dominant regulator of proliferation of malignant gliomas in vitro. These tumor cells possess very high intrinsic PKC activity in comparison to non- transformed glia, and this high activity correlates strongly with their proliferation rates in vitro. This high activity offers a potential target for chemotherapeutic inhibition in these tumors. The central theme of the present proposal will explore the molecular basis of PKC activity within these tumors, with direct clinical extrapolation of the work being to test the utility of targeting PKC activity for growth inhibition of gliomas in vivo. Such a proposal spans a Spectrum of investigation from molecular biology to clinical studies. The preliminary objective of the proposal will examine the molecular basis for the high PKC activity, which may represent a genetic alteration in the PKC System itself, or may reflect the enzyme being driven by up-regulated growth factor systems known to exist in these tumors. To differentiate these possibilities, analysis of the PKC isozymes in gliomas will be performed at the protein (western blotting and flow cytometry), mRNA (northern blotting), and DNA (Southern blot) levels. As an extension of pre-clinical studies, inhibitors of PKC will be utilized in rat glioma model to study chemotherapeutic potential in vivo; preliminary work has demonstrated that such inhibitors may extend survival in this model. Optimal routes of administration and dosing kinetics must be established. Further pre-clinical animal studies will be the utilization of gene therapy to target specific overexpressed PKC isozyme activity in the malignant glioma cell. In addition to further experience with molecular biological techniques, this phase will represent a major developmental component for the applicant. The clinical correlate of the work is an ongoing study administering high dose Tamoxifen (which inhibits PKC, a property distinct from estrogen receptor blockade) to patients harboring recurrent malignant gliomas.
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