Targeting KRAS mutation-bearing lung cancer in vivo by pulmonary surfactant-adenovirus-mediated gene transfer.

Abstract

Pulmonary surfactant has been used as a carrier to deliver a therapeutic virus to dysfunctional lung cells that reside within an intricate lung structure. To investigate whether pulmonary surfactant enhances the efficacy of intratracheal instillation of a therapeutic virus to target KRAS mutation-bearing lung cancer in vivo, we developed a recombinant adenovirus that induces cell death only in lung cancer cells and injected the adenovirus into a mouse model of KRAS mutation-positive lung cancer intratracheally with and without surfactant. A therapeutic adenovirus that induces cell death only in lung cancer cells was constructed by combining a cancer-specific human telomerase reverse transcriptase (hTERT) promoter fused to CCAAT/enhancer-binding protein alpha (CEBPα) with a modified lung-specific Clara cell-specific 10-kDa protein (CC10) promoter fused to cytotoxic adenovirus type 5 early region 1A (E1A). CEBPα is induced only in cancer cells and activates the CC10 promoter, which in turn induces cytotoxic E1A, and causes cell death only in lung cancer cells in vitro. This adenovirus was intratracheally administered to the model mice (CCSP-rtTA/Tet-op-K-Ras4bG12D bitransgenic mice) in the presence and absence of pulmonary surfactant. Intratracheally administered therapeutic adenovirus with pulmonary surfactant spread to airways, as well as to the alveolar region of the lung, and caused a reduction of lung tumors developed. The therapeutic adenovirus without pulmonary surfactant spread only to airways and was ten-fold less effective in tumor reduction. Here, we demonstrate that pulmonary surfactant is an efficient tool to intratracheally deliver a therapeutic virus to treat KRAS mutation-positive lung cancer in vivo.

• Authors: Takuya Fukazawa, Yutaka Maeda, Junji Matsuoka, Toshiro Ono, Katsumi Mominoki, Tomoki Yamatsuji, Kaoru Shigemitsu, Ichiro Morita, Ichiro Murakami, Hirotoshi Tanaka, Mary L Durbin, Yoshio Naomoto
• Journal: Anticancer research (Anticancer Res) Vol. 30 Issue 12 Pg. 4925-35 (Dec 2010) ISSN: 1791-7530 [Electronic] Greece
• PMID: 21187472 (Publication Type: Journal Article)

Chemical References

• Adenovirus E1A Proteins
• Pulmonary Surfactants

Topics

• Adenocarcinoma (genetics, therapy, virology)
• Adenoviridae (genetics, physiology)
• Adenovirus E1A Proteins (genetics)
• Animals
• Breast Neoplasms
• Cattle
• Cell Line, Tumor
• Female
• Gene Transfer Techniques
• Genes, ras
• Genetic Therapy (methods)
• Genetic Vectors (genetics)
• HeLa Cells
• Humans
• Lung Neoplasms (genetics, therapy, virology)
• Mice
• Mice, Inbred ICR
• Mice, Transgenic
• Mutation
• Oncolytic Virotherapy (methods)
• Promoter Regions, Genetic
• Pulmonary Surfactants (administration & dosage)