title: Targeting lung cancer using an infectivity enhanced CXCR4-CRAd.
abstract: Conventional treatments are not adequate for the majority of lung cancer patients. Conditionally replicating adenoviruses (CRAds) represent a promising new modality for the treatment of neoplastic diseases, including non-small cell lung cancer. Specifically, following cellular infection, the virus replicates selectively in the infected tumor cells and kills the cells by cytolysis. Next, the progeny virions infect a new population of surrounding target cells, replicate again and eradicate the infected tumor cells while leaving normal cells unaffected. However, to date, there have been two main limitations to successful clinical application of these CRAd agents; i.e. poor infectivity and poor tumor specificity. Here we report the construction of a CRAd agent, CRAd-CXCR4.RGD, in which the adenovirus E1 gene is driven by a tumor-specific CXCR4 promoter and the viral infectivity is enhanced by a capsid modification, RGD4C. This agent CRAd-CXCR4.RGD, as expected, improved both of the viral infectivity and tumor specificity as evaluated in an established lung tumor cell line and in primary tumor tissue from multiple patients. As an added benefit, the activity of the CXCR4 promoter was low in human liver as compared to three other promoters regularly used for targeting tumors. In addition, this agent has the potential of targeting multiple other tumor cell types. From these data, the CRAd-CXCR4.RGD appears to be a promising novel CRAd agent for lung cancer targeting with low host toxicity.
authors.affiliation: Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, AL 35291, USA.
authors.forename: Zeng B
authors.initials: ZB
authors.lastname: Zhu
authors.forename: Angel A
authors.initials: AA
authors.lastname: Rivera
authors.forename: Sharmila K
authors.initials: SK
authors.lastname: Makhija
authors.forename: Baogen
authors.initials: B
authors.lastname: Lu
authors.forename: Minghui
authors.initials: M
authors.lastname: Wang
authors.forename: Miiru
authors.initials: M
authors.lastname: Izumi
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cerfolio
authors.forename: Mariam A
authors.initials: MA
authors.lastname: Stoff-Khalili
authors.forename: Fen
authors.initials: F
authors.lastname: Zhou
authors.forename: Koichi
authors.initials: K
authors.lastname: Takayama
authors.forename: Gene P
authors.initials: GP
authors.lastname: Siegal
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000628:therapy*; D005822:Genetic Vectors; D006801:Humans; D008099:Liver / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D019718:Receptors, CXCR4 / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014779:Virus Replication
chemical_list: D019718:Receptors, CXCR4