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Inhibition of Oncogenic K-ras Signaling by Aerosolized Gene Delivery in a Mouse Model of Human Lung Cancer¹

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [H-Y. L., Y-A. S., J. I. L., K. A. H., L. M., J. M. K.]; Molecular Cardiology Research Institute, New England Medical Center, Boston, Massachusetts 02111 [T. F.]; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030 [B. E. G.]; and Howard Hughes Medical Institute, Center for Cancer Research, and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 [T. J.]

Purpose: Transfer of growth-suppressive genes to lung tumors has therapeutic potential, but effective delivery techniques have not been developed. Here, we investigated gene delivery to lung tumors by aerosolization of adenoviral vectors incorporated into calcium phosphate precipitates.

Experimental Design: To investigate the efficacy of this delivery method in normal and neoplastic lung, an adenoviral vector expressing ß-galactosidase was administered by jet nebulization to K-ras^LA1 mice, which develop lung adenocarcinomas through activation of a latent allele carrying mutant K-ras(G12D). Furthermore, we investigated whether aerosolized delivery of Ad-MKK4 (KR), an adenoviral vector expressing dominant-negative mutant mitogen-activated protein kinase kinase 4(MKK4), can block Ras-dependent signaling in K-ras^LA1 mice.

Results: After a single administration, ß-galactosidase was detected in lung tissue for up to 21 days, and expression was much greater in tumors than in normal lung tissue. MKK4 was activated in the lungs of K-ras^LA1 mice, and aerosolized treatment with Ad-MKK4 (KR) decreased c-Jun-NH₂-terminal kinase but not extracellular signal- regulated kinase activity, providing evidence that MKK4 was selectively inhibited.

Conclusions: These findings demonstrate a novel approach to targeting oncogenic pathways in lung tumors by aerosolized gene delivery.

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