Systemic IFN-β gene therapy results in long-term survival in mice with established colorectal liver metastases
Hiroomi Tada, … , James M. Wilson, Francis R. Spitz
Hiroomi Tada, … , James M. Wilson, Francis R. Spitz
Published July 1, 2001
Citation Information: J Clin Invest. 2001;108(1):83-95. https://doi.org/10.1172/JCI9841.
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Article

Systemic IFN-β gene therapy results in long-term survival in mice with established colorectal liver metastases

Abstract

Most patients succumbing to colorectal cancer fail with liver-predominant metastases. To make a clinical impact in this disease, a systemic or whole-liver therapy may be required, whereas most cancer gene therapy approaches are limited in their ability to treat beyond local disease. As a preclinical model for cancer gene therapy, recombinant adenovirus containing the human IFN-β (hIFN-β) cDNA was delivered systemically in nude mouse xenograft models of human colorectal cancer liver metastases. The vector targeted hepatocytes that produced high levels of hIFN-β in the liver, resulting in a profound apoptotic response in the tumors and significant tumor regression. hIFN-β gene therapy not only resulted in improved survival and long-term cure in a micrometastatic model, but provided similar benefits in a clinically relevant gross disease model. A similar recombinant adenovirus containing the murine IFN-β (mIFN-β) cDNA also resulted in a therapeutic response and improved survival in syngeneic mouse models of colorectal cancer liver metastases. Depletion studies demonstrate a contribution of natural killer cells to this therapeutic response. The toxicity of an adenoviral vector expressing murine IFN-β in a syngeneic model is also presented. These encouraging results warrant further investigation of the use of cancer gene therapy for targeting metastatic disease.

Authors

Hiroomi Tada, David J. Maron, Eugene A. Choi, James Barsoum, Hanqin Lei, Qing Xie, Wenbiao Liu, Lee Ellis, A. David Moscioni, John Tazelaar, Stephen Fawell, Xiao Qin, Kathleen J. Propert, Alan Davis, Douglas L. Fraker, James M. Wilson, Francis R. Spitz

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H5.110CMVhIFN-β treatment does not inhibit the growth of a murine colore...
H5.110CMVhIFN-β treatment does not inhibit the growth of a murine colorectal cell line in an intrahepatic microscopic disease athymic nude mouse liver metastases model; however, H5.110CMVmIFN-β, which expresses murine IFN-β, inhibits the growth of murine colorectal liver tumors and improves survival in a liver metastases model. (a) CT26 cells were directly injected in the livers of athymic nude mice. On day 5, mice were randomized to receive PBS, H5.010CMVβ-gal, or H5.110CMVhIFN-β via tail vein injection. On day 19, livers were harvested for tumor volume measurement. Each point represents a single animal, and mean tumor volume is indicated by the large cross. (b) CT26 cells were injected directly in the livers of BALB/c mice. On day 5, mice were randomized to receive PBS, H5.010CMVβ-gal, or H5.110CMVmIFN-β (AdmIFN-β) via tail vein injection. On day 19, livers were harvested for tumor volume measurement (P = 0.0001). (c) CT26 cells were injected into the spleens of BALB/c mice. On day 5, mice were randomized to receive PBS, H5.010CMVβ-gal, or H5.110CMVmIFN-β via tail vein injection, or daily intraperitoneal injections of 10,000 U of recombinant mIFN-β protein. Mice were sacrificed when they became moribund by preestablished criteria, and their survival curves were plotted. (d) CT26 cells were injected subcutaneously into the flanks of BALB/c mice. On day 5, mice were randomized to receive PBS, H5.010CMVβ-gal, or H5.110CMVmIFN-β via tail vein injection. Tumors were measured twice per week and tumor volumes were estimated assuming an ellipsoid shape (P < 0.05).