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Selective induction of tumor-associated antigens in murine pulmonary vasculature using double-targeted adenoviral vectors

Gene Therapy volume 12, pages 1042–1048 (2005)Cite this article

Abstract

Targeted therapies directed to tumor-associated antigens are being investigated for the treatment of cancer. However, there are few suitable animal models for testing the ability to target these tumor markers. Therefore, we have exploited mice transgenic for the human coxsackie and adenovirus receptor (hCAR) to establish a new model for transient expression of human tumor-associated antigens in the pulmonary vasculature. Systemic administration of Ad in hCAR mice resulted in an increase in transgene expression in the lungs compared to wild-type mice, as determined using a luciferase reporter gene. To reduce transgene expression in the liver, the predominant organ of ectopic Ad localization and transgene expression following systemic administration, we utilized the endothelial-specific flt-1 promoter, which resulted in a further increased lung-to-liver ratio of luciferase expression. Administration of an adenoviral vector encoding the tumor-associated antigen carcinoembryonic antigen (CEA) under transcriptional control of the flt-1 promoter resulted in selective expression of this antigen in the pulmonary vasculature of hCAR mice. Feasibility of targeting to expressed CEA was subsequently demonstrated using adenoviral vectors preincubated with a bifunctional adapter molecule recognizing this tumor-associated antigen, thus demonstrating utility of this transient transgenic animal model.

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Acknowledgements

We thank Dr S Petterson for his kind gift of the transgenic hCAR mice, and the transgenic facility at the University of Alabama at Birmingham for maintaining and screening the transgenic mice. We also thank CR Stockard for his technical assistance with the immunohistochemistry for CEA. This work was supported by the following grants: 1 P01 HL076540, P01 HL075640-01, RO1 HL67962, RO1 AG021875, W81XWH-04-1-0025, MDA3590, and NHMRC (Australia). MA Preuss and MJ Passineau are further supported by T32 HL07553. WE Grizzle is supported by the Breast and Ovarian SPORES at UAB (CA 89019-04 and CA-83591-05, respectively).

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Authors and Affiliations

  1. Division of Human Gene Therapy, Departments of Medicine, Surgery, Pathology and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL, USA

    M Everts, S-A Kim-Park, M A Preuss, M J Passineau, J N Glasgow, A V Pereboev, P J Mahasreshti, W E Grizzle & D T Curiel

  2. Department of Obstetrics and Gyneacology, University of Alabama at Birmingham, Birmingham, AL, USA

    P J Mahasreshti

  3. Department of Thoracic Medicine, Chest Clinic, Royal Adelaide Hospital, Adelaide, Australia

    P N Reynolds

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  1. M Everts
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Everts, M., Kim-Park, SA., Preuss, M. et al. Selective induction of tumor-associated antigens in murine pulmonary vasculature using double-targeted adenoviral vectors. Gene Ther 12, 1042–1048 (2005). https://doi.org/10.1038/sj.gt.3302491

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