Prodrug activating transcription unit gene therapy is one of several promising approaches to @entity5 gene therapy. Combining that approach with conditionally replication-competent viral vectors that are truly @entity5 specific has been an important objective of recent work. In this study, we report the construction of a new conditionally replication-competent bicistronic adenoviral vector in which the @entity5538 deaminase (CD) gene and the E1a gene are driven by the @entity40085 @entity5 -specific promoter (AdLpCDIRESE1a). A similar vector driven by the @entity2834 promoter has also been constructed (AdCMVCDIRESE1a) as a control. We have carried out in vitro @entity137 in @entity0 , and in vivo efficacy studies with these vectors in an animal model of @entity694 . While the addition of the AdLpCDIRESE1a vector to established @entity5 cell lines showed significant @entity137 in @entity5 cells derived from @entity189 of the breast (MCF-7), colon (HTB-38) and ovary (Ovcar 5), no significant @entity137 was seen in explant cultures of normal @entity1 mammary epithelial cells (HMEC) exposed to this vector. The addition of @entity4895 ( @entity10498 ) significantly increased the @entity137 in an additive fashion of both the AdLpCDIRESE1a and AdCMVCDIRESE1a vectors as well as that of the AdLpCD replication incompetent vector to established @entity5 cell lines. However, no significant @entity137 was observed with the addition of 5FC to explant cultures of normal @entity1 mammary epithelial cells that had been exposed to the @entity40085 -driven vectors. Studies with mixtures of infected and uninfected @entity5 cell lines showed that the established @entity5 cell lines infected with the AdLpCDIRESE1a vector generated significant @entity137 to surrounding uninfected cells (the "bystander effect") even at a ratio of 0.25 of infected cells to infected + uninfected cells in the presence of 5FC. The injection of the AdLpCDIRESE1a vector into subcutaneous deposits of @entity1 @entity5 nodules in the @entity19 was potentiated by administering 5-FC by intraperitoneal injection. This treatment resulted in a decreased @entity5 size and a decreased @entity5 cell growth rate. The @entity19 treated with a combination of the AdLpCDIRESE1a vector intratumoral injection and intraperitoneal 5FC injections lived much longer than the other experimental groups exposed to the viral vector alone or to the combination of the intratumoral AdLpCD replication incompetent vector injections plus intraperitoneal 5-FC injections. These encouraging results with our newly constructed AdLpCDIRESE1a vector suggest a need for further study of its utility in a preclinical model of intracavitary therapy of @entity298 .

Cytotoxic effect of replication-competent adenoviral vectors carrying @entity40085 promoter regulated E1A and XXXX deaminase genes in @entity0 .

@entity1 :: ('9606', 'Species') :: ['human'] @entity137 :: ('MESH:D064420', 'Disease') :: ['toxicity', 'cytotoxicity'] @entity0 :: ('MESH:D001943', 'Disease') :: ['carcinomas of the breast, ovary and colon'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'cancer'] @entity10498 :: ('CHEBI:5100', 'Chemical') :: ['5FC'] @entity19 :: ('10090', 'Species') :: ['mice', 'nude mice'] @entity40085 :: ('3936', 'Gene') :: ['L-plastin'] @entity189 :: ('MESH:D002277', 'Disease') :: ['carcinomas'] @entity4895 :: ('MESH:D005437', 'Chemical') :: ['5-fluorocytosine'] @entity5538 :: ('MESH:D003596', 'Chemical') :: ['cytosine'] @entity2834 :: ('12305', 'Species') :: ['CMV'] @entity694 :: ('MESH:D003110', 'Disease') :: ['colon cancer'] @entity298 :: ('MESH:D010538', 'Disease') :: ['pleural or peritoneal carcinomatosis']
@entity5538 :: (MESH:D003596,Chemical) :: ['cytosine']
