title: Enhanced antitumor effect of the combination of tumstatin gene therapy and gemcitabine in murine models.
abstract: Targeting tumor endothelium is an important strategy for cancer therapy. We evaluated the effectiveness of gene therapy, that is, intramuscular delivery of plasmid DNA encoding tumstatin (pSecTag2B-tum), combined with gemcitabine administration in vitro and in vivo, using colon carcinoma (CT26) and Lewis lung carcinoma (LLC) murine models. The in vitro growth-inhibitory and proapoptotic effects of gemcitabine and/or tumstatin on human umbilical vein endothelial cells (HUVECs) and mouse endothelial cells (SVEC4-10), respectively, were assessed. in vitro, conditioned medium from pSecTag2B-tum-transfected COS cells inhibited the growth of endothelial cells but not of CT26 or LLC cells, whereas gemcitabine inhibited the growth of both endothelial cells and CT26 and LLC cells. Mice bearing subcutaneously established CT26 or LLC tumors received pSecTag2B-tum alone or in combination with gemcitabine to assess tumor growth inhibition. in vivo, combined treatment with pSecTag2B-tum and gemcitabine significantly decreased tumor growth through increased inhibition of tumor angiogenesis and increased tumor cell apoptosis compared with either agent alone. Enhanced antiproliferative and proapoptotic activity of the combination therapy on tumor-associated endothelial cells was calculated to be significant. This study suggests that 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. A combination of these agents could be used in future studies and translated into the clinical setting.
authors.affiliation: National Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yao
authors.forename: Qiu-Ming
authors.initials: QM
authors.lastname: He
authors.forename: Ling
authors.initials: L
authors.lastname: Tian
authors.forename: Fei
authors.initials: F
authors.lastname: Xiao
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.forename: Ru
authors.initials: R
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Jian-Mei
authors.initials: JM
authors.lastname: Hou
authors.forename: Lian
authors.initials: L
authors.lastname: Wang
authors.forename: Xian-Cheng
authors.initials: XC
authors.lastname: Cheng
authors.forename: Yan-Jun
authors.initials: YJ
authors.lastname: Wen
authors.forename: Bin
authors.initials: B
authors.lastname: Kan
authors.forename: Jiong
authors.initials: J
authors.lastname: Li
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Qiao
authors.initials: Q
authors.lastname: Zhou
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
mesh_terms: D020533:Angiogenesis Inhibitors / Q000096:biosynthesis / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D001324:Autoantigens / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000628:therapy*; D045744:Cell Line, Tumor; D024141:Collagen Type IV / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000628:therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001324:Autoantigens; D024141:Collagen Type IV; D011994:Recombinant Proteins; C057112:type IV collagen alpha3 chain; D003841:Deoxycytidine; D000093542:Gemcitabine