Genetic Radiotherapy of Prostate Cancer
Annual rept. 1 Dec 2002-30 Nov 2003
ALABAMA UNIV IN BIRMINGHAM
Pagination or Media Count:
A goal of this proposal is to achieve a high intratumoral concentration of 5-fluorouracil 5-FU via molecular chemotherapy employing genetically modified adenoviral Ad vectors encoding the genes for somatostatin receptor subtype 2 SSTr2 and cytosine deaminase CD which converts the prodrug 5-fluorocytosine 5-FC to 5-FU under control of the cyclooxygenase-2 Cox-2 tumor-specific promoter. The purpose of Specific Aim 1 was to develop, validate, and evaluate genetically modified Ad vectors that will increase expression levels of both SSTr2 and CD. We proposed to initially evaluate two novel two-gene Ad vectors 1 a native fiber Ad AdCMVCDCMVSSTr2 and 2 Ad under control of the Cox-2 promoter expressing CD and SSTr2. We have produced several vectors including AdCox-2LCDCox-2LS STr2, AdCox-2LS STr2Cox-2LCD, AdRGDCox- 2LCDCox-2LSSTr2, and AdRGDCox-2LCDCox-2LSSTr2. The vectors we developed were tested for SSTr2 and CD expression employing membrane receptor binding in vitro with 125I-somatostatin and 99mTc-P2O45 that binds to SSTr2, conversion of 5-FC to 5-FU, and cytotoxicity against Ad infected cells in the presence of 5-FC. The vectors were evaluated in vivo for SSTr2 expression and CD expression. Efforts are continuing to produce ROD modified vectors expressing CD and SSTr2 under control of the Cox-2L promoter to be used for therapy in local and metastatic models.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research