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 Google Scholar Articles by Shashkova, E. V. Articles by Barry, M. A. PubMed PubMed Citation Articles by Shashkova, E. V. Articles by Barry, M. A.

Macrophage Depletion Combined with Anticoagulant Therapy Increases Therapeutic Window of Systemic Treatment with Oncolytic Adenovirus

¹ Division of Infectious Diseases, Department of Internal Medicine, ² Department of Immunology, ³ Department of Molecular Medicine, ⁴ Translational Immunovirology Program, ⁵ Cancer Center, Mayo Clinic, Rochester, Minnesota; and ⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas

Requests for reprints: Michael A. Barry, Mayo Clinic, 200 First Street SW, Rochester, MN. Phone: 507-266-9090; Fax: 507-255-2811; E-mail: mab{at}mayo.edu.

Key Words: oncolytic virotherapy • adenovirus • xenograft • systemic therapy • Kupffer cells • anticoagulants

Liver tropism of systemically delivered adenoviruses (Ad) represents a considerable challenge for their use as anticancer therapeutics. More than 90% of i.v. injected Ad is rapidly taken up by the liver leading to hepatotoxicity, reduced virus uptake by target tumor tissue, and diminished therapeutic efficacy. The lack of clinical activity of systemically given oncolytic Ad demands for better understanding and improvement of virus pharmacokinetics. We studied the effects of Ad "detargeting" from liver macrophages (Kupffer cells) and hepatocytes on toxicity and anticancer efficacy using a nonattenuated oncolytic Ad expressing enhanced green fluorescent protein-firefly luciferase fusion protein (Ad-EGFPLuc). Kupffer cell depletion before i.v. injection of Ad-EGFPLuc increased transgene expression in the liver 40.7-fold on day 3 after the injection indicating compensatory enhancement of hepatocyte transduction due to increased bioavailability of the virus. Pretreatment of mice with the anticoagulant drug warfarin to block blood factor–dependent binding of the virus to hepatocytes markedly reduced luciferase expression in the liver and mediated the corresponding decrease of hepatotoxicity in mice with intact and depleted liver macrophages. Combined depletion of Kupffer cells and pretreatment with warfarin before a single i.v. injection of Ad-EGFPLuc significantly reduced tumor growth and prolonged survival of nude mice bearing subcutaneous xenografts of aggressive human hepatocellular carcinoma. The improved antitumor activity correlated with enhanced transgene expression and virus spread in the tumors. These data suggest that detargeting oncolytic Ad from liver macrophages and hepatocytes is an effective strategy to increase the therapeutic window for therapy against disseminated tumor sites. [Cancer Res 2008;68(14):5896–904]