Antitumor effects of an adenovirus expressing antisense insulin-like growth factor I receptor on human lung cancer cell lines.
Insulin-like growth factors (IGFs) are often essential for the maintenance of the malignant phenotype, and in lung cancer the IGF-I receptor (IGF-Ir) is often expressed at high levels. Stable transfection of antisense plasmids expressing the first 300 bp of the IGF-Ir reduces the tumorigenicity of a variety of tumor cell lines and has been reported to induce systemic antitumor effects on established, non-gene-modified tumors in animal model systems. We have constructed an adenovirus expressing an antisense IGF-Ir (Ad-IGF-Ir/as) in an attempt to develop these observations into a clinical therapeutic approach. A single transduction by Ad-IGF-Ir/as (at a multiplicity of infection of 10:1) decreased the IGF-Ir number by about 50% in human lung cancer cell lines NCI H460 and SCC5, as measured by an 125I-labeled IGF-I competitive binding assay. After the transduction of these human lung cancer cell lines by Ad-IGF-Ir/as, the soft agar clonogenicity was reduced by 84%. The i.p. treatment of nude mice bearing established i.p. NCI H460 cells resulted in prolonged survival compared to that of nude mice treated with a reporter virus. These results suggest that Ad-IGF-Ir/as has a therapeutic effect on established human lung cancer xenografts and may represent an effective and practical cancer gene therapy strategy.
Lee
C T
CT
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas 75235, USA.
Wu
S
S
Gabrilovich
D
D
Chen
H
H
Nadaf-Rahrov
S
S
Ciernik
I F
IF
Carbone
D P
DP
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000362:Agar; D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000628:therapy* / Q000648:ultrastructure*; D002455:Cell Division / Q000187:drug effects; D002999:Clone Cells; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007457:Iodine Radioisotopes; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy* / Q000648:ultrastructure*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D014161:Transduction, Genetic; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D007457:Iodine Radioisotopes; D016376:Oligonucleotides, Antisense; D007334:Insulin-Like Growth Factor I; D000362:Agar; D017526:Receptor, IGF Type 1