The use of cytokine gene therapy combined with suicide gene/prodrug can enhance bystander effect by reinforcing immune function. Chen et al. [29] injected recombined
adenovirus expressed both IL-2 gene and HSV-tk gene to colon carcinoma model with hepatic metastasis, and found that the link of tk gene and IL-2 possess was more sufficient than individual gene therapy. We demonstrated that the therapy of a combining suicide gene (HSV-tk and MCP-1) significantly selleck chemical improved the antitumor efficiency GSK1210151A on SKOV3 cells by bicistronic recombinant replication-defective retroviruses vector pLXSN/tk-MCP-1 constructed in our lab. The bicistronic pLXSN co-expressing tk and MCP-1 linked by a bicistronic unit including poliomyelitis virus IRES was designed by proteinaceous translation initiation model inside chain of eukaryotic cell. The single upstream promoter can transcribe the same mRNA from two genes, and then the gene in the upstream
is translated in eukaryocyte cap-dependent manner, while the downstream gene can be translated and expressed under PND-1186 ic50 the control of IRES in cap-independent manner, avoiding the influence on expression of the two genes at the regulation level of transcription. The maximum concentration of MCP-1 and the result of chemotactic index of MCP-1-mediated migration showed that SKOV3/tk-MCP-1 could secrete MCP-1 possessed chemotactic activity. Furthermore, Ribonucleotide reductase our study showed a
strong bystander effect was observed in the system of SKOV3/tk-MCP-1 + GCV. MCP-1 is one of the major chemoattractants for mononuclear macrophage which can directly eradicate tumor cells, the importance is MCP-1 significantly induced a low survival rate when transduced cells and untransduced cells are cultured together in specific ratios as a immuno-modulator. Boosted bystander effect by immunal inflammatory system showed 10% tk + can induce a 70% tumor cells death rate. Combined HSV-tk with MCP-1 gene therapy is a powerful approach for the treatment of ovarian cancer. They not only could play their antitumor role respectively, but also could creat synergistic action which could enhance the anti-tumor immune reactions. Many immune effector cells aggregate to tumor site via the expression of MCP-1 activity and provoke nonspecific immune reaction and specific immunity, not only boosting the cytotoxic effect of GCV but also enhancing immune reaction to reinforce the bystander effect. In order to explore the synergic antineoplastic mechanism and the influence on tumorous biological behavior of combined HSV-tk and MCP-1 gene, we investigated apoptosis and cell cycle.