The long range goal of these studies is to prepare efficient and stable tools for the transfer of foreign genes into tumor cells to study the mechanism of action of tumor suppressor genes and to develop approaches to gene therapy for some kinds of tumors. We wish to use the models of the retinoblastoma (Rb) and p53 genes to examine the effect of expression of wild type and mutant forms of these tumor suppressor genes on cell phenotype. We wish also to determine the mechanism and clinical usefulness of changes in growth and tumorigenicity properties of cells in which the expression of these genes is restored by viral vector gene transfer.
Our specific aims are: 1. to modify and improve Moloney murine leukemia virus (MoMLV)-based vectors, 2. to develop an alternative retroviral vector, based on simian sarcoma- associated virus (SSAV), 3. determine the phenotypic effect of restored Rb expression on tumor cell phenotype, 4. develop alternative gene transfer tools, including adeno-associated virus (AAV) and liposomes, 5. study the feasibility of in vivo suppression of existing tumors by efficient delivery in vivo of the Rb tumor suppressor gene, 6. to extend the Rb suppression to a variety of cells in which defects of p53 are associated with the tumor phenotype.
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