Effects of genetic blockade of the insulin-like growth factor receptor in human colon cancer cell lines.
OBJECTIVE
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.
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001798:Blood Proteins / Q000494:pharmacology; D015197:Carcinogenicity Tests; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D018076:DNA, Complementary; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015316:Genetic Therapy; D019073:HT29 Cells; D018869:Heat-Shock Response / Q000502:physiology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology; D013752:Tetracycline / Q000494:pharmacology; D014162:Transfection
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001798:Blood Proteins; D018076:DNA, Complementary; D011518:Proto-Oncogene Proteins; D017526:Receptor, IGF Type 1; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D013752:Tetracycline