Abstract
ObjectiveThe efficiency of HSV-tk/GCV system is not high because of insufficient gene transfer and incompletely initiative of host antineoplastic potency. The present study was designed to assess the antitumor efficacy of tk-MCP-1 on ovarian cancer in vitro and vivo.MethodsA novel bicistronic expression system can help to improve the expression level of a gene in a stable manner. pLXSN/tk-MCP-1 co-expressing tk and MCP-1 genes was constructed using a pLXSN retroviral vector and an internal ribosome entry site sequence by restriction enzyme. Western blot was performed to determine tk and MCP-1 expression in the infected SKOV3. The GCV-sensitively tumoricidal activities of SKOV3/tk-MCP-1 with or without monocytes were compared to those of SKOV3 expressing HSV-tk or MCP-1. We investigated the growth of subcutaneous tumors in SCID mice immuno-reconstituted, and evaluated the antitumor effect of MCP-1 in conjunction with suicide gene.ResultsThe significant GCV-sensitively tumoricidal activity of pLXSN/tk-MCP-1 was observed when compared with those of pLXSN/tk, pLXSN/MCP-1 and pLXSN/neo, especially when monocytes were added. The growth of subcutaneous tumors in SCID mice immuno-reconstituted was markedly suppressed by co-delivery of HSV-tk and MCP-1 genes, and the enhanced antitumor effect was associated with the recruitment of monocytes.ConclusionThese results demonstrated pLXSN/tk-MCP-1 presented an enhanced antitumor effects on ovarian cancer by orchestration of immune responses.
Highlights
Ovarian cancer is the leading cause of death from gynecologic cancers
By Restriction Enzyme cutting site, EcoRI - XhoI internal ribozyme entry site (IRES) fragment of poliomyelitis virus, we got linear pLXSN. It was inserted into the herpes simplex virus thymidine kinase gene fragment from pWZLneotkglyCD with BamHI-EcoRI to generate the tk-IRES-neo, and pLXSN/tk was obtained by insertion of tk-IRES-neo into Linear pLXSN. pLXSN fragment combined with MCP-1 gene fragment to generate pLXSN/MCP-1
SKOV3 cells were infected with the high titre recombinant retrovirus, while SKOV3 tansfected pLXSN/neo was used as the control group
Summary
Ovarian cancer is the leading cause of death from gynecologic cancers. Every year, approximately 200,000 women are diagnosed with ovarian cancer and more than 100,000 women died of ovarian cancer around the world [1,2]. Due to inherent and acquired chemoresistance of ovarian cancer, the effect of current therapies for advanced or metastatic ovarian cancer is far from satisfying [3]. This underscores the imperative to adopt new strategies to fight against ovarian cancer effectively. Suicide gene therapy is one of these strategies with antitumor effect [4,5]. Its efficacy for the treatment of cancer is limited because of the insufficient gene transfection and insufficient induction of host immunity [6,7,8]
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