title: 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.affiliation: Department of General Surgery, Kawasaki Medical School, Okayama 700-8505, Japan. FukazawaT@aol.com
authors.forename: Takuya
authors.initials: T
authors.lastname: Fukazawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Maeda
authors.forename: Junji
authors.initials: J
authors.lastname: Matsuoka
authors.forename: Toshiro
authors.initials: T
authors.lastname: Ono
authors.forename: Katsumi
authors.initials: K
authors.lastname: Mominoki
authors.forename: Tomoki
authors.initials: T
authors.lastname: Yamatsuji
authors.forename: Kaoru
authors.initials: K
authors.lastname: Shigemitsu
authors.forename: Ichiro
authors.initials: I
authors.lastname: Morita
authors.forename: Ichiro
authors.initials: I
authors.lastname: Murakami
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Mary L
authors.initials: ML
authors.lastname: Durbin
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Naomoto
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000628:therapy / Q000821:virology; D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D001943:Breast Neoplasms; D002417:Cattle; D045744:Cell Line, Tumor; D005260:Female; D018014:Gene Transfer Techniques; D011905:Genes, ras; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000628:therapy* / Q000821:virology; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009154:Mutation; D050130:Oncolytic Virotherapy / Q000379:methods*; D011401:Promoter Regions, Genetic; D011663:Pulmonary Surfactants / Q000008:administration & dosage*
chemical_list: D017500:Adenovirus E1A Proteins; D011663:Pulmonary Surfactants