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 mainten ance of the malignant phenotype, and in lung cancer the IGF-I receptor (IGF-Ir) is often expressed at high levels. Stable transfection of an tisense 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-modifie d tumors in animal model systems. We have constructed an adenovirus ex pressing an antisense IGF-Ir (Ad-IGF-Ir/as) in an attempt to develop t hese observations into a clinical therapeutic approach. A single trans duction by Ad-IGF-Ir/as (at a multiplicity of infection of 10:1) decre ased the IGF-Ir number by about 50% in human lung cancer cell lines NC I H460 and SCC5, as measured by an I-125-labeled IGF-I competitive bin ding assay. After the transduction of these human lung cancer cell lin es by Ad-IGF-Ir/as, the soft agar clonogenicity was reduced by 84%. Th e i.p. treatment of nude mice bearing established i.p. NCI H460 cells resulted in prolonged survival compared to that of nude mice treated w ith a reporter virus. These results suggest that Ad-IGF-Ir/as has a th erapeutic effect on established human lung cancer xenografts and may r epresent an effective and practical cancer gene therapy strategy.