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Evaluation of transformation defective E1A mutants for the use as antineoplastic transgenes for the gene therapy of Kaposi sarcomas, melanomas, and other AIDS-associated tumors


The use of multifunctional genomic wild type Adenovirus (Ad) 5 E1A as an antineoplastic transgene has the disadvantage that both, the 13S- and the 12S E1A product, have the potential to transform primary cells.

Therefore we constructed mutants of the Ad5- and, for the first time, of the Ad12-13S-E1A-cDNA, where different sequences that are associated with transformation were deleted. Interestingly, the tumor suppressor activity of some of these mutants was not reduced as compared with the wild type protein. Due to its multifunctional antitumorigenic, antimetastatic, and apoptotis-inducing functions, E1A can be considered as a broad range antineoplastic transgene that suppresses the growth of different kinds of tumors, thereby exhibiting a low toxicity for normal tissue. In the first part of our project we will construct therapeutic vectors with transformation defective E1A-mutants that bear the highest antineoplastic potential (based, e.g., on the pVAX plasmid). These vectors will contain the herpesvirus VP22-sequence, allowing intercellular traffic of the resulting fusion proteins. The antineoplastic properties of these constructs will be examined in different HHV8 positive and negative cell lines and transplanted Kaposi sarcomas and/or melanomas in nude mice experiments. Transduction efficiency in vitro and in vivo and suppression of tumor malignancy will be analyzed after local (intratumorigenic) and systemic administration of the vectors. In addition, the putative suppression of the latent HHV-8/KSHV-genes LT1 and 2 by the 12S-splice product of our E1A mutants that should induce apoptosis in the respective tumor cells will be analyzed. Moreover, the induction of apoptosis will too be analyzed in HHV-8 negative tumor cell lines. Goal of this project is the development of high efficiency E1A-derived antineoplastic transgenes.

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