[Oncostatin M gene therapy in mice bearing lung adenocarcinoma xenograft using a hypoxia/radiation dual-sensitive promoter]

Abstract

Objective: To improve the efficacy of radiogenetic therapy for lung cancer, a hypoxia/radiation dual-sensitive promoter was constructed to enhance the expression of oncostatin M (OSM) in transfected cells exposed to radiation under hypoxia.

Methods: The chimeric promoter HRE-Egr was generated by insertion of hypoxia response elements (HREs) upstream of the Early growth response gene-1 (Egr-1) promoter. OSM expression vector was constructed by cloning HRE-Egr promoter upstream of OSM gene, which was transfected into A549 cells. The expression of OSM in transfected cells exposed to irradiation and(or) hypoxia was analyzed, and the relative survival rate of transfected cells exposed to the above conditions was tested. To examine the efficacy of this HRE-Egr-OSM gene therapy in vivo, the tumor suppression effects were investigated in 40 nude mice bearing lung adenocarcinoma xenograft.

Results: Expression of OSM gene in transfected cells exposed 6 Gy irradiation was markedly increased under hypoxia. A gene therapy experiment in vitro showed that the survival rate of transfected cells exposed to radiation under hypoxia was obviously decreased with comparison of cells under normoxia. HRE-Egr promoter transfected tumors regressed significantly after a combination therapy of irradiation and HRE-Egr transfection in all mice (n = 10), and six tumors disappeared in 3 weeks without any side effects.

Conclusion: The data indicate that tumor targeted expression of OSM gene under the control of a hypoxia/radiation dual-sensitive promoter represents a novel strategy for safe and effective gene therapy of lung carcinoma and might have clinical application in the future.