Inhibition of oncogenic K-ras signaling by aerosolized gene delivery in a mouse model of human lung cancer.
OBJECTIVE
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.


METHODS
To investigate the efficacy of this delivery method in normal and neoplastic lung, an adenoviral vector expressing beta-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, beta-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-NH(2)-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.
Lee
Ho-Young
HY
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Suh
Young-Ah
YA
Lee
Janet I
JI
Hassan
Khaled A
KA
Mao
Li
L
Force
Thomas
T
Gilbert
Brian E
BE
Jacks
Tyler
T
Kurie
Jonathan M
JM
D000230:Adenocarcinoma / Q000235:genetics / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics; D000336:Aerosols; D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D005091:Exons / Q000235:genetics; D005799:Genes, Dominant; D017930:Genes, Reporter; D011905:Genes, ras; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D007763:Lac Operon; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy*; D048670:MAP Kinase Kinase 4; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000502:physiology; D017354:Point Mutation; D015398:Signal Transduction / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D000336:Aerosols; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases