Inhibition of human non-small cell lung tumors by a c-Met antisense/U6 expression plasmid strategy.
Gene Ther
; 11(3): 325-35, 2004 Feb.
Article
em En
| MEDLINE
| ID: mdl-14737093
ABSTRACT
c-Met is a receptor tyrosine kinase whose activation by hepatocyte growth factor (HGF) can lead to transformation and tumorigenicity in a variety of tumors. We investigated the effects of suppressing c-Met protein expression in human non-small cell lung tumors. Expression plasmids containing either sense or antisense sequences of the human c-met gene were constructed under control of the U6 snRNA promoter. A U6 control plasmid was also constructed that did not contain any c-met sequence. These constructs have been examined both in vitro and in an in vivo tumor xenograft model. The c-Met protein was downregulated by 50-60% in two lung cancer cell lines that were transiently transfected with the c-Met antisense versus U6 control. Tumor cells treated with the c-Met antisense construct also show decreased phosphorylation of c-Met and MAP kinase when exposed to exogenous HGF. Lung cancer cells were grown as xenografts in mice and treated by intratumoral liposome-mediated transfer of the c-Met sense, antisense or U6 control plasmids. The treatment of lung tumors with c-Met antisense versus U6 control plasmid resulted in the downregulation of the c-Met protein expression, a 50% decrease in tumor growth over a 5-week treatment period and an increased rate of apoptosis. These results suggest that targeting the HGF/c-Met pathway may be an effective novel strategy to treat lung cancer patients.
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Base de dados:
MEDLINE
Assunto principal:
Terapia Genética
/
Elementos Antissenso (Genética)
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Carcinoma Pulmonar de Células não Pequenas
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Proteínas Proto-Oncogênicas c-met
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Neoplasias Pulmonares
Idioma:
En
Ano de publicação:
2004
Tipo de documento:
Article