Enhanced Antitumor Effect Of The Combination Of Tumstatin Gene Therapy And Gemcitabine In Murine Models

Targeting the tumor endothelium is an important strategy for cancer therapy. We evaluated the effectiveness of combined treatment with the gene therapy by the intramuscular delivery of plasmid DNA encoding tumstatin (pSecTag2B-tum) and gemcitabine in vitro and in vivo using colon carcinoma (CT26) and Lewis lung carcinoma (LLC) murine models. The in vitro growth inhibitory and pro-apoptotic effects of gemcitabine and/or tumstatin on human umbilical vein endothelial cells (HUVECs) and mouse endothelial cells (SVEC4-10) were assessed respectively. In vitro the conditioned medium from pSecTag2B-tum-transfected COS cells inhibited the growth of endothelial cells but not CT26 or LLC cells, while gemcitabine inhibited the growth of both endothelial cells, CT26 and LLC cells. Mice bearing subcutaneously established CT26 or LLC tumors received pSecTag2B-tum alone and in combination with gemcitabine to assess tumor growth inhibition. In vivo combined treatment with pSecTag2B-tum and gemcitabine significantly decreased tumor growth through inhibition of tumorangiogenesis and increase of tumor cells apoptosis compared with either agent alone. An enhanced effect on anti-proliferative and proapoptotic activity was calculated with the combination of the two agents on tumor-associated endothelial cells. This study suggests that the combined treatment by the intramuscular delivery of plasmid DNA encoding tumstatin and gemcitabine augments tumor growth inhibition by suppressing angiogenesis and enhancing apoptosis in murine models. The combination between these agents could be used in future studies and translated into the clinical setting.