Incorporating the survivin promoter in an infectivity enhanced CRAd-analysis of oncolysis and anti-tumor effects in vitro and in vivo

摘要: Conditionally replicating adenoviruses (CRAds) represent a promising new modality for the treatment of cancer. A key contribution in this regard was introduction tumor-selective viral replication amplification initial inoculum. Specifically, following cellular infection, virus replicates selectively infected tumor cells and kills by cytolysis. Next, progeny virions infect surrounding target cells, replicate eradicate leaving normal unaffected. However, to date there have been two limitations clinical application these CRAd agents; i.e., both infectivity specificity are poor. Survivin protein is novel member inhibitor apoptosis (IAP) family, which plays an important role survival cancer progression malignancies. Previous data shown survivin promoter has high activities multiple with low activity mouse liver. In study, we propose improved agent circumvent obstacles. We constructed agent, CRAd-Survivin-RGD, contains (either short version, S-S, or long S-L) drive E1 gene expression capsid modification RGD4C specifically enhance agents. Both agents (S-S showed rates breast cell line, MDA-MB-361, human liver, thus signifying phenotype 'tumor on/liver off'. cytocidal experiments, demonstrated effect on lines, including MDA-MB-231; glioma D65, melanoma MEL-28; mesothelioma, Meso2374. The results also growth dramatically inhibited intertumoral administration (MDA-MB-361) xenograft animal model. These clearly demonstrate that CRAd-Survivin-RGD potential therapeutic many, but not all, cancers.