(Applicant's Description) Gene therapeutic approaches to cancer need to consider the multi-genetic nature of the disease. Enhancement of ionizing radiation (IR) toxicity through improve understanding of molecular mechanisms of tumor cell radio- responsiveness, involving gene transfer experimentation, is the goal of this Program. It considers the complexity of cellular responses and concentrates on genes and cell functions contribution to cellular radio- sensitivity. As many cellular IR responses remain to be defined, each project has a strong mechanistic remain to be defined, each project has a strong mechanistic investigational component beyond exploring the potential of gene therapeutic application. The expression modulation of individual genes represent the most specific approach to identifying functions of genes/gene products specifically modulating cellular radio- responsiveness. The projects involve in vitro and in vivo experimentation as well as clinical investigation. The Program utilizes a spectrum of neoplastic cell, carcinomas (Projects 1-3), malignant gliomas (projects 3 and 4) and lymphomatous blasts (Project 5). Specific study topics include: (a) Receptor (EGFR)-mediated initiation of signal transduction at the plasma membrane and downstream signaling effects; (b) regulation of the cell cycle by Ca2+ and regulatory proteins; (c) Effects of ER on the modulation of the existing balance of cells between proliferative and apoptotic responses through relative differences in signals along the proliferation and stress pathways, including roles of the protein kinase C (PKC) modulator (bryostatin 1, Bryo), p53, apoptosis modifiers (Bcl-2/Ba), and manipulation of DNA synthesis (HSV-TK; (d) exploratory clinical application of the PKC modulator Bryo because of its potential of improving the effects of total body irradiation an important of autologous bone marrow transplantation. Besides the common scientific theme, the Program is further linked by common technologies provided by the adenovirus, animal/cellular assays, and administrative cores. While the genetic experimentation will elucidate specific mechanisms of cellular radio-responsiveness. Future experimentation will have to determine whether gene transfer or novel therapeutic low Mr compounds will be most effective.
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