Abstract | BACKGROUND & 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.
|
Authors | Yasushi 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 |
Journal | Gastroenterology
(Gastroenterology)
Vol. 123
Issue 4
Pg. 1191-204
(Oct 2002)
ISSN: 0016-5085 [Print] United States |
PMID | 12360481
(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
|