This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wang, Z.-G. Articles by Seth, P. Search for Related Content PubMed PubMed Citation Articles by Wang, Z.-G. Articles by Seth, P.

¹ Laboratory of Gene Therapy, Evanston Northwestern Healthcare Research Institute and Department of Medicine, Evanston Hospital, Northwestern University, Evanston, Illinois; ² Laboratory of Pathology, Hokkaido University, Sapporo, Hokkaido, Japan; and ³ Canji, Inc., San Diego, California

Requests for reprints: Prem Seth, Laboratory of Gene Therapy, Evanston Northwestern Healthcare Research Institute, Evanston Hospital, Room B624, 2650 Ridge Avenue, Evanston, IL 60201. Phone: 847-570-2317; Fax: 847-733-5256. E-mail: pseth{at}northwestern.edu

In recent years, adenoviruses that selectively replicate in tumor cells have been developed. However, there is a tremendous need to improve their anticancer efficacy. We wish to investigate whether a strategy that combines the oncolytic effects of an adenoviral vector with simultaneous expression of soluble form of transforming growth factor-ß type II receptor (sTGFßRII) offers a therapeutic advantage. We chose to target TGF-ßs because they play a pivotal role in late-stage tumorigenesis by enhancing tumor invasion and metastasis. A sTGFßRII cDNA was cloned in conditionally replicating adenoviral vector rAd-sTRII and in a replication-deficient adenovirus Ad-sTRII. Infection of MDA-MB-231 breast cancer cells with rAd-sTRII or Ad-sTRII followed by Western blot analysis indicated the expression of diffused glycosylated forms of sTGFßRII that were also secreted into the extracellular medium. The secreted proteins were shown to bind with TGF-ß and antagonize TGF-ß–induced p38 mitogen-activated protein kinase activity. However, marked differences in the replication potential of rAd-sTRII and Ad-sTRII were observed in breast tumor cells. Infection of MDA-MB-231 cells with rAd-sTRII resulted in cytotoxicity and significant increase in the adenoviral titers that were comparable with a wild-type adenovirus dl309. However, Ad-sTRII was much less toxic to the tumor cells, and the viral titers of Ad-sTRII remained relatively unchanged. These results suggest that the infection of breast tumor cells with conditionally replicating adenoviral vector rAd-sTRII produced sTGFßRII that can abrogate TGF-ß signaling while maintaining the replication potential of the virus, indicating that rAd-sTRII could be a potential anticancer agent. [Mol Cancer Ther 2006;5(2):367–73]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: The current address for W. Zhao is the Department of Microbiology, Columbia University, New York, New York.

Received 4/25/05; revised 10/31/05; accepted 11/22/05.