title: Liposomal insulin promoter-thymidine kinase gene therapy followed by ganciclovir effectively ablates human pancreatic cancer in mice.
abstract: PDX1 is overexpressed in pancreatic cancer, and activates the insulin promoter (IP). Adenoviral IP-thymidine kinase and ganciclovir (TK/GCV) suppresses human pancreatic ductal carcinoma (PDAC) in mice, but repeated doses carry significant toxicity. We hypothesized that multiple cycles of liposomal IP-TK/GCV ablate human PDAC in SCID mice with minimal toxicity compared to adenoviral IP-TK/GCV. SCID mice with intraperitoneal human pancreatic cancer PANC-1 tumor implants were given a single cycle of 35 µg iv L-IP-TK, or four cycles of 1, 10, 20, 30, or 35 µg iv L-IP-TK (n = 20 per group), followed by intraperitoneal GCV. Insulin and glucose levels were monitored in mice treated with four cycles of 35 µg iv L-IP-TK. We found that four cycles of 10-35 µg L-IP-TK/GCV ablated more PANC-1 tumor volume compared to a single cycle with 35 µg. Mice that received four cycles of 10 µg L-IP-TK demonstrated the longest survival (P < 0.05), with a median survival of 126 days. In comparison, mice that received a single cycle of 35 µg L-IP-TK/GCV or GCV alone survived a median of 92 days and 68.7 days, respectively. There were no significant changes in glucose or insulin levels following treatment. In conclusion, multiple cycles of liposomal IP-TK/GCV ablate human PDAC in SCID mice with minimal toxicity, suggesting non-viral vectors are superior to adenoviral vectors for IP-gene therapy.
authors.affiliation: David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: James X
authors.initials: JX
authors.lastname: Wu
authors.affiliation: David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: Shi-He
authors.initials: SH
authors.lastname: Liu
authors.affiliation: Mary Crowley Cancer Research Centers, Dallas, TX, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Nemunaitis
authors.affiliation: David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. Electronic address: CBrunicardi@mednet.ucla.edu.
authors.forename: F Charles
authors.initials: FC
authors.lastname: Brunicardi
mesh_terms: D000256:Adenoviridae / Q000201:enzymology; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D015774:Ganciclovir / Q000627:therapeutic use*; D015316:Genetic Therapy; D006801:Humans; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000473:pathology; D008081:Liposomes; D008297:Male; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy*; D011401:Promoter Regions, Genetic; D051381:Rats; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection; D047368:Tumor Burden; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000998:Antiviral Agents; D007328:Insulin; D008081:Liposomes; D014764:Viral Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir
keywords: Gene therapy; Insulin promoter; PDX1; Pancreatic cancer; Thymidine kinase