Specific growth inhibition of small-cell lung cancer cells by adenovirus vector expressing antisense c-kit transcripts.
Antisense methods to control aberrant gene expression have been investigated as therapeutic strategies. A proto-oncogene c-kit, which encodes a transmembrane tyrosine kinase, is overexpressed in some malignancies, including small-cell lung cancer (SCLC), and is thought to be involved in their pathogenesis. To test the feasibility of using adenovirus vectors for antisense strategies and to target c-kit in SCLC therapy, we constructed replication-deficient recombinant adenovirus vectors which express fragments of c-kit transcripts in antisense (Ad.kitAS) or sense orientation (Ad.kitS: control). In vitro infection of SBC-1 cells, which are c-Kit protein-producing SCLC cells, by these vectors resulted in the expression of artificial c-kit transcripts. The Ad.kitAS-infected SBC-1 cells showed reductions in the amount of c-Kit protein. As expected, at 10 days after infection (1 multiplicity of infection), Ad.kitAS-infected SBC-1 cells showed approximately 40% growth inhibition compared to uninfected or Ad.kitS-infected cells in vitro. Such a significant growth inhibition by Ad.kitAS was not induced in SBC-5 cells, which are SCLC cells producing no c-Kit protein. These results demonstrate the usefulness of adenovirus vectors in antisense strategies, and the feasibility of targeting c-kit in the therapy of c-Kit-producing SCLC.
Yamanishi
Y
Y
Second Department of Internal Medicine, Hiroshima University School of Medicine, Japan.
Maeda
H
H
Hiyama
K
K
Ishioka
S
S
Yamakido
M
M
D000256:Adenoviridae / Q000235:genetics*; D001483:Base Sequence; D018288:Carcinoma, Small Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016373:DNA, Antisense / Q000627:therapeutic use*; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D016373:DNA, Antisense; C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit