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Genetic Radiotherapy of Prostate Cancer

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Annual rept. 1 Dec 2001-30 Nov 2002

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The purpose of the research carried out in the first year of this project was to develop a system to express the therapeutic genes cytosine deaminase CD and somatostatin receptor SSTr2 in localized and disseminated prostate cancer cells with sufficient selectivity for cancer gene therapy. The specificity of these vectors for prostate cancer will be improved by combining transductional targeting of Ad with the target cell-specific expression of the therapeutic gene. This will be achieved by utilizing the tumor-specific promoter, cyclooxygenase-2 COX-2, to drive the transcription of the SSTr2 and CD genes By employing this double targeting maneuver, we expect to achieve a much higher level of vector specificity cell killing would only occur as a result of two independent events - cell infection and transgene expression. Although both events are not perfectly tumor-specific, their combination will lead to a desired synergistic effect of specificity In other words, if the vector randomly infects non-target normal cells, the cell killing will not take place, since the SSTr2 and CD expression will be limited primarily to prostate tumor cells. The liver is the predominant site of Ad vector localization after systemic administration, and as a consequence is at risk when Ad vectors containing suicide genes such as CD ectopically localize to this site. Thus, a promoter with both tumor specificity and minimal transcriptional activity in hepatocytes would be ideal for cancer gene therapy. The hypothesis of the grant was that the COX-2 promoter is a promising candidate tumor-specific promoter for prostate cancer, since it reveals low hepatic activity and toxicity, and shows high tumor activity in established cell lines. Combined with the targeted Ad vectors described in the application, the COX-2 promoter may be an ideal candidate tumor-specific promoter for GRITSmolecular chemotherapy of disseminated hormone refractory prostate cancer

Subject Categories:

  • Biochemistry
  • Genetic Engineering and Molecular Biology
  • Anatomy and Physiology

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