Suppression of pancreatic tumor growth in the liver by systemic administration of the TRAIL gene driven by the hTERT promoter.
Local and locoregional administration of adenovectors expressing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene has been demonstrated to be useful in treating established tumors in animals. Moreover, expression of the TRAIL gene from the human telomerase reverse transcriptase (hTERT) promoter can be used to prevent possible liver toxicity of the TRAIL gene. However, it remains unknown whether systemic administration of the TRAIL-expressing adenovector can be used for cancer therapy. Here, we showed that a combination of TRAIL gene therapy and gemcitabine, the first-line chemotheraphy agent for pancreatic cancer, had a synergistic effect on the induction of apoptosis in human pancreatic cancer cell lines in vitro. Systemic administration of an adenovector that contains an insertion of integrin-binding motif argine-glycine-aspartate (RGD) in the HI loop of the adenoviral fiber protein and expresses the human TRAIL gene from the hTERT promoter (designated Ad/TRAIL-F/RGD) suppressed the growth of human pancreatic tumor cells inoculated in the liver of nu/nu nude mice. Furthermore, Ad/TRAIL-F/RGD in combination with gemcitabine suppressed the tumor growth of pancreatic cancer in the liver more than did treatments consisting of each agent alone. No obvious liver toxicity was detected in any of the treatment groups. Our results suggest that TRAIL gene therapy in combination with gemcitabine might be a useful therapeutic approach for treating metastatic pancreatic cancers.
Jacob
Dietmar
D
Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center Houston, Texas 77030, USA.
Davis
John J
JJ
Zhang
Lidong
L
Zhu
Hongbo
H
Teraishi
Fuminori
F
Fang
Bingliang
B
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004357:Drug Synergism; D015316:Genetic Therapy; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy*; D011401:Promoter Regions, Genetic; D053221:TNF-Related Apoptosis-Inducing Ligand; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D000093542:Gemcitabine
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D003841:Deoxycytidine; C047981:arginyl-glycyl-aspartic acid; D019098:Telomerase; D000093542:Gemcitabine