GENETIC MANIPULATION OF TUMOR RADIORESISTANCE

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DESCRIPTION: (Applicant's Description) Certain drugs act synergistically with radiation to increase cell killing. However, the specific sensitization of tumor cells to radiation over that of normal cells has been a limiting factor where one can potentially make major advances is to radio-sensitize tumor cells through genetic manipulation (transient gene therapy) with highly infectious recombinant adenoviruses. The basic concept is to introduce a gene into tumor normal cellular proteins to allow for tumor-specific chemical radio-sensitization. In this proposal we will specifically radio-sensitize p53 wild-type and mutant rat glioma cells in vitro and in vivo and human glioma cells in vitro by delivering the Herpes simplex Virus (HSV) thymidine kinase (TK) gene with the nucleosides which are specifically infectious adenovirus and exposing the cells to modified nucleosides which are specifically phosphorylated by HSV-TK and incorporated into tumor cell DNA. Incorporation of the halogenated pyrimidines bromodeoxycytidine and iododeoxycytidine, and the DNA chain-terminator acyclovir is expected to radio-sensitize the cells. The p53 suppressor gene is likely to influence this radio-sensitivity and in close collaboration with Project 4, we will investigate the role of p53 in HSV-TK-mediated radio-sensitization of gliomas. Because a direct correlation exists between cell proliferation, DNA incorporation of modified nucleosides, and extent of radio- sensitization, attempts will also be made to stimulate cell proliferation by genetically manipulating the expression of thioredoxin, a growth factor and transcriptional activator associated with ribonucleotide reductase which is intimately linked to nucleoside biosynthesis and DNA synthesis. Results from these studies will increase our understanding of how to efficiently delivery recombinant adenovirus in situ with the purpose of chemically radio-sensitize gliomas.