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Interferon receptor expression regulates the antiproliferative effects of interferons on cancer cells and solid tumors

In addition to antiviral effects, Type I interferons (IFN) have potent antiproliferative and immunomodulatory activities. Because of these properties IFNs have been evaluated as therapeutics for the treatment of a number of human diseases, including cancer. Currently, IFNs have been shown to be effi...

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Published in:International journal of cancer 2004-08, Vol.111 (1), p.32-42
Main Authors: Wagner, T. Charis, Velichko, Sharlene, Chesney, Steven K., Biroc, Sandra, Harde, Dean, Vogel, David, Croze, Ed
Format: Article
Language:English
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Summary:In addition to antiviral effects, Type I interferons (IFN) have potent antiproliferative and immunomodulatory activities. Because of these properties IFNs have been evaluated as therapeutics for the treatment of a number of human diseases, including cancer. Currently, IFNs have been shown to be efficacious for the treatment of only a select number of cancers. The reason for this is unclear. Recent evidence has demonstrated that some cancer cell types seem to be defective in their ability to respond to IFN. It has been suggested that defects in IFN signaling is one mechanism by which cancer cells escape responsiveness to Type I IFNs and growth control in general. We report that transfection and enhanced expression of the Type I IFN receptor chain (IFNAR2c) in 3 different human cancer cell lines markedly increases the sensitivity of these cells to the antiproliferative effects of IFNs. In cancer cells transfected with IFNAR2c, dose response curves demonstrate a significant decrease in the concentrations of IFN required to achieve maximum cell death. Furthermore, in these transfected cells, we observe a significant increase in the number of cells undergoing apoptosis, as measured by DNA fragmentation and Caspase 3 activation. In addition, using an in vivo xenograft tumor model we show an increase in the effectiveness of systemically delivered Betaseron™ in decreasing tumor burden in animals in which solid tumors were generated from IFNAR2c transfected cells. These data show that specific regulation of IFN receptor expression can play a major role in determining the clinical outcome of IFN‐based cancer therapeutics by regulating the relative sensitivity of cancer cells to IFN‐dependent growth control. © 2004 Wiley‐Liss, Inc.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.20236