Combined endostatin and TRAIL gene transfer suppresses human hepatocellular carcinoma growth and angiogenesis in nude mice.
Endostatin can inhibit tumor growth by blocking angiogenesis, whereas tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) may function as a soluble cytokine to selectively kill cancer cells without toxicity to most normal cells. To establish the combined anti-tumor therapeutic effect of endostatin and soluble TRAIL (sTRAIL), we performed intra-tumoral human endostatin and sTRAIL gene transfer using plasmid pVAX1 as a vector in a nude mouse model of human liver cancer. For subcutaneously inoculated human BEL7402 cancer, co-expression of both transgenes conferred marked anti-tumor activity with a significant reduction in tumor vessel density and an increase in apoptotic rates, which was accompanied with a strong activation of caspase-3. Importantly, combination therapy employing one-half dose of endostatin and sTRAIL plasmids was more effective than single endostatin or sTRAIL therapy. These results indicate that a pVAX1-mediated combinatorial antiangiogenic and proapoptotic gene therapy approach involving endostatin and sTRAIL can be an effective novel form of treatment for human liver cancer.
Zhang
Yan
Y
Department of Pharmacology, Medical School of Shandong University, Jinan, China.
Qu
Zhong-Hua
ZH
Cui
Min
M
Guo
Chun
C
Zhang
Xiu-Mei
XM
Ma
Chun-Hong
CH
Sun
Wen-Sheng
WS
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D019556:COS Cells; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D043169:Endostatins / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D020287:In Situ Nick-End Labeling; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010957:Plasmids / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016896:Treatment Outcome; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D043169:Endostatins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human