Abstract
BackgroundFree flap-mediated gene therapy in the tumor bed following surgical resection is a promising approach in cancer targeted treatment of residual disease. We investigated the selective killing efficacy of a lentivirus-mediated cytosine deaminase-thymidine kinase (CDglyTK) gene in transplanted breast cancer delivered into a free flap by intra-artery perfusion.MethodsProliferation, apoptosis, and cell cycle of rat SHZ-88 breast cancer cells transfected with a lentivirus-mediated CD/TK gene were measured following treatment with ganciclovir and 5-flucytosine in vitro. A model of residual disease of breast cancer in a rat superficial inferior epigastric artery (SIEA) flap model was used to study the therapeutic potential of a double suicide CD/TK and prodrug system in vivo.ResultsKilling efficacy of the double suicide CD/TK and prodrug system on SHZ-88 cells was mediated by increased apoptosis and cell cycle arrest at the G1 phase with significant bystander effect. Following recombinant lentivirus transfection of rat SIEA flap by intra-artery perfusion, CD/TK gene expression was limited to the flap, and the volume and weight of transplanted tumors were significantly reduced without observable toxicity.ConclusionsSIEA flaps transfected with a lentivirus-mediated CDglyTK gene by intra-artery perfusion effectively suppress transplanted breast tumor growth without obvious systemic toxic effects in rats.
Highlights
Free flap-mediated gene therapy in the tumor bed following surgical resection is a promising approach in cancer targeted treatment of residual disease
Regarding determination of virus titer, we found two cells infected with LV-Cytosine deaminase-thymidine kinase (CDglyTK) and one cell transfected with LV-green fluorescence protein (GFP) expressed GFP using 10− 5 μL recombined lentivirus
Lentivirus-mediated transduction efficiency and expression of CDglyTK gene in SHZ-88 cells To examine lentivirus-mediated gene transfer efficiencies, cells from the SHZ-88 rat breast cancer cell line were infected with LV-CMV-CDglyTK and LV-CMVGFP at various multiplicities of infection (MOI), and GFP gene expression was observed by fluorescence microscopy
Summary
Free flap-mediated gene therapy in the tumor bed following surgical resection is a promising approach in cancer targeted treatment of residual disease. We investigated the selective killing efficacy of a lentivirus-mediated cytosine deaminase-thymidine kinase (CDglyTK) gene in transplanted breast cancer delivered into a free flap by intra-artery perfusion. Radical resection is the mainstay of treatment for breast cancer, there is a high risk of locoregional tumor recurrence after ablative surgery [3]. When such excision takes place, it can result in extensive soft tissue defects and loss of important aesthetic form that often needs microvascular free-tissue transfer for reconstruction, which has gained worldwide acceptance as the primary. VDEPT may be suited for delivery through a free flap because the production of cytotoxic metabolites will be distributed directly over the tumor bed
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