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Effects of genetic blockade of the insulin-like growth factor receptor in human colon cancer cell lines.

AbstractBACKGROUND & AIMS:
Insulin-like growth factor (IGF)-I receptor (IGF-Ir) signaling is required for maintenance of growth and tumorigenicity of several tumor types. We have previously shown successful therapy in a lung cancer xenograft model using an adenovirus expressing antisense IGF-Ir. In this study, we sought to better dissect the mechanism and develop potentially more effective IGF-Ir-targeted therapeutics by developing and testing tetracycline-regulated and recombinant adenoviruses expressing dominant negative receptors.
METHODS:
Truncated IGF-I receptors (IGF-Ir/tf; 482 and 950 amino acids long, respectively [IGF-Ir/482st and IGF-Ir/950st]) were cloned into tetracycline-regulated vectors and recombinant adenoviruses and then studied in colorectal cancer cells. We assessed the effect of IGF-Ir/tf on signaling blockade, colony formation, stress response (serum starvation and heat), chemotherapy-induced apoptosis, and in vivo therapeutic efficacy in xenografts.
RESULTS:
Activation of IGF-Ir/tf expression by withdrawal of tetracycline 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/tf expression increased chemotherapy-induced apoptosis, and this combination therapy was very effective against tumors in mice. These findings were confirmed in a therapy model against established tumors using adenoviruses expressing IGF-Ir/tf. Moreover, IGF-Ir/482st was more effective than IGF-Ir/950st because of its bystander effect.
CONCLUSIONS:
Anti-tumor activity of IGF-Ir/tf is mediated through inhibition of Akt-1 and enhances the efficacy of chemotherapy. Adenovirus IGF-Ir/482st may be a useful anticancer therapeutic for colorectal carcinoma.
AuthorsYasushi Adachi, Choon-Taek Lee, Keith Coffee, Noboru Yamagata, Joyce E Ohm, Kyung-Ho Park, Mikhail M Dikov, Sorena R Nadaf, Carlos L Arteaga, David P Carbone
JournalGastroenterology (Gastroenterology) Vol. 123 Issue 4 Pg. 1191-204 (Oct 2002) ISSN: 0016-5085 [Print] United States
PMID12360481 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Anti-Bacterial Agents
  • Antineoplastic Agents
  • Blood Proteins
  • DNA, Complementary
  • Proto-Oncogene Proteins
  • Receptor, IGF Type 1
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Tetracycline
Topics
  • Adenoviridae (genetics)
  • Animals
  • Anti-Bacterial Agents (pharmacology)
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects, physiology)
  • Blood Proteins (pharmacology)
  • Carcinogenicity Tests
  • Cell Division (drug effects)
  • Colonic Neoplasms (genetics, physiopathology, therapy)
  • DNA, Complementary
  • Female
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Genetic Therapy
  • HT29 Cells
  • Heat-Shock Response (physiology)
  • Humans
  • Mice
  • Mice, Nude
  • Protein Serine-Threonine Kinases (metabolism)
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Receptor, IGF Type 1 (genetics)
  • Signal Transduction (physiology)
  • Tetracycline (pharmacology)
  • Transfection

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