title: Genetic blockade of the insulin-like growth factor-I receptor: a promising strategy for human pancreatic cancer.
abstract: Pancreatic cancer is one of the most lethal malignant tumors. Insulin-like growth factor (IGF)-I receptor (IGF-Ir) signaling is required for maintenance of growth and tumorigenicity of many tumors, but this pathway has not been well studied in pancreatic cancer. We have shown previously successful therapy in colorectal and lung cancer xenograft models using recombinant adenoviruses expressing dominant negative IGF-I receptors. In this study, we sought to better dissect the mechanism of action of this virus and determine whether IGF-Ir targeted adenoviruses represent potentially effective therapeutics for human pancreatic cancer cells. Truncated IGF-I receptors (IGF-Ir/dn; 482 and 950 amino acids long, respectively, IGF-Ir/482st and IGF-Ir/950st) that function as dominant negative inhibitor were cloned into recombinant adenoviruses and used to treat human pancreatic cancer cells. We assessed the effect of IGF-Ir/dn on signaling blockade, growth, stress response, chemotherapy, radiation-induced apoptosis, and in vivo therapeutic efficacy in xenografts. IGF-Ir/dn expression suppressed tumorigenicity both in vitro and in vivo and up-regulated stressor-induced apoptosis. It effectively blocked both IGF-I and IGF-II-induced activation of Akt-1. IGF-Ir/dn expression increased radiation and chemotherapy-induced apoptosis, and the combination therapy of IGF-Ir/dn with chemotherapy was very effective against tumors in mice. In an i.p. model, IGF-Ir/dn therapy reduced dissemination and prolonged survival times. Moreover, IGF-Ir/482st was more effective than IGF-Ir/950st because of its bystander effect. The antitumor activity of IGF-Ir/dn is mediated through inhibition of Akt-1 and enhances the efficacy of chemotherapy. Adenovirus-IGF-Ir/482st may be a useful anticancer therapeutic for pancreatic cancer.
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University, S-1 W-16, Chuo-ku, Sapporo 060-8543, Japan.
authors.forename: Yongfen
authors.initials: Y
authors.lastname: Min
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Adachi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Hideto
authors.initials: H
authors.lastname: Ito
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
authors.forename: Choon-Taek
authors.initials: CT
authors.lastname: Lee
authors.forename: Sorena
authors.initials: S
authors.lastname: Nadaf
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy / Q000628:therapy*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D018076:DNA, Complementary; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D017526:Receptor, IGF Type 1; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005472:Fluorouracil