Enhanced antitumor effect of the combination of tumstatin gene therapy and gemcitabine in murine models.
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.
Yao
Bin
B
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.
He
Qiu-Ming
QM
Tian
Ling
L
Xiao
Fei
F
Jiang
Yu
Y
Zhang
Ru
R
Li
Gang
G
Zhang
Lin
L
Hou
Jian-Mei
JM
Wang
Lian
L
Cheng
Xian-Cheng
XC
Wen
Yan-Jun
YJ
Kan
Bin
B
Li
Jiong
J
Zhao
Xia
X
Hu
Bin
B
Zhou
Qiao
Q
Zhang
Ling
L
Wei
Yu-Quan
YQ
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
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