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Ad5-sge-reic/dkk-3 mtg-201

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A replication incompetent adenoviral vector type 5 (Ad5) encoding the tumor suppressor gene dickkopf-3 (DKK3; reduced expression in immortalized cells; REIC; Dickkopf WNT signaling pathway inhibitor 3), and containing the super gene expression (SGE) system, composed of the triple tandem enhancer sequences of human telomerase reverse transcriptase (hTERT), simian virus 40 (SV40) and cytomegalovirus (CMV), with potential immunostimulating and antineoplastic activities. Upon intratumoral (IT) injection and transfection of Ad5-SGE-REIC/Dkk-3 MTG-201, tumor cells express REIC/DKK3 protein. This may result in the activation of c-Jun-NH2-kinase (JNK) and ultimately lead to apoptosis via B-cell lymphoma-2 (Bcl2) suppression and caspase-3 activation. Increased expression of REIC/DKK3 in cancer cells may lead to an induction of tumor cell apoptosis and a reduction in tumor cell growth, while sparing normal, healthy cells expressing endogenous REIC/DKK3. In addition, the tumor cell killing promotes a cytotoxic T-lymphocyte (CTL)-mediated immune response, thereby further killing any remaining REIC-deficient, untransfected tumor cells. The SGE system, also called C-TSC (CMV promoter driving the triple tandem enhancer sequences of hTERT, SV40 and CMV), enhances gene expression compared to more conventional adenoviral vectors. REIC/DKK3 is expressed by healthy cells, but expression is reduced or absent in many cancer cells due to REIC/DKK3 gene defects. As REIC/DKK3 plays a key role in tumor cell apoptosis, the absence of the REIC protein in tumor cells prevents tumor cell apoptosis.

 

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