Original communication| Volume 135, ISSUE 4, P427-436, April 2004

Interferon-β gene therapy improves survival in an immunocompetent mouse model of carcinomatosis



      Interferon-β (IFNβ) has multiple antitumor effects; however, its use has been limited by its short half-life in vivo. This limitation may be overcome by IFNβ gene therapy. We evaluated adenovirus-IFNβ therapy in an immunocompetent mouse model of carcinomatosis.


      Mice that were treated intraperitoneally 5 days after tumor (mouse ovarian teratoma) inoculation with an adenoviral vector that contains the mouse IFNβ gene (Ad-IFNβ), control adenoviral vector or saline solution. Mice were monitored for multiple outcome measures and toxicity. To determine the mechanism of antitumor effect, flow cytometry of ascites fluid was performed to differentiate immune cell populations. Nitric oxide in ascites fluid was measured with an electrochemical microsensor.


      Tumor burden was decreased and survival was prolonged (P<.001) in the Ad-IFNβ group after a single treatment of 3.3×108 plaque-forming units, with acceptable toxicity. By flow cytometry, an increase in the proportion of natural killer cells (from less than 2% of the gated population to more than 8%; P = .024) and an increase in macrophages were seen in the treated animals. Although there was a trend toward increased levels of nitric oxide in Ad-IFNβ treatment groups, it was not statistically significant.


      IFNβ gene therapy results in decreased tumor burden and improved survival in an aggressive, immunocompetent mouse model of carcinomatosis. This therapy warrants further evaluation as a treatment for disseminated peritoneal cancer.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Loggie B.W.
        • Fleming R.A.
        • McQuellon R.P.
        • Russell G.B.
        • Geisinger K.R.
        Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy for disseminated peritoneal cancer of gastrointestinal origin.
        Am Surgeon. 2000; 66: 561-568
        • Hendren S.H.
        • Hahn S.M.
        • Spitz F.R.
        • Bauer T.W.
        • Rubin S.C.
        • Zhu T.
        • et al.
        Phase II trial of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors.
        Ann Surg Oncol. 2001; 8: 65-71
        • Fish E.N.
        • Uddin S.
        • Korkmaz M.
        • Majchrzak B.
        • Druker B.J.
        • Platanias L.C.
        Activation of a CrkL-Stat5 signaling complex by Type I interferons.
        J Biol Chem. 1999; 274: 571-573
        • Der S.D.
        • Zhou A.
        • Williams B.R.G.
        • Silverman R.H.
        Identification of genes differentially regulated by interferon α, β, or using oligonucleotide arrays.
        Proc Natl Acad Sci USA. 1998; 95: 15623-15628
        • Albini A.
        • Marchisone C.
        • DelGrosso F.
        • Benelli R.
        • Masiello L.
        • Tacchetti C.
        • et al.
        Inhibition of angiogenesis and vascular tumor growth by interferon-producing cells: a gene therapy approach.
        Am J Pathol. 2000; 156: 1381-1393
        • Dong Z.
        • Greene G.
        • Pattaway C.
        • Dinney C.P.
        • Eue I.
        • Lu W.
        • et al.
        Suppression of angiogenesis, tumorigenicity, and metastasis by human prostate cancer cells engineered to produce interferon-β.
        Cancer Res. 1999; 59: 872-879
        • Lu W.
        • Fidler I.J.
        • Dong Z.
        Eradication of primary murine fibrosarcomas and induction of systemic immunity by adenovirus-mediated interferon-β gene therapy.
        Cancer Res. 1999; 59: 5202-5208
        • Qin X.Q.
        • Tao N.
        • Dergay A.
        • Moy P.
        • Fawell S.
        • Davis A.
        • et al.
        Interferon-β gene therapy inhibits tumor formation and causes regression of established tumors in immune-deficient mice.
        Proc Natl Acad Sci USA. 1998; 95: 14411-14416
        • Xie K.
        • Bielenberg D.
        • Huang S.
        • Xu L.
        • Salas T.
        • Juang S.H.
        • et al.
        Abrogation of tumorigenicity and metastasis of murine and human tumor cells by transfection with the murine IFN-β gene: possible role of nitric oxide.
        Clin Cancer Res. 1997; 3: 2283-2294
        • Xu L.
        • Xie K.
        • Fidler I.J.
        Therapy of human ovarian cancer by transfection with the murine interferon β gene: role of macrophage-inducible nitric oxide synthase.
        Hum Gene Ther. 1998; 9: 2699-2708
        • Dong Z.
        • Juang S.H.
        • Kumar R.
        • Eue I.
        • Xie K.
        • Bielenberg D.
        • et al.
        Suppression of tumorigenicity and metastasis in murine UV-2237 fibrosarcoma cells by infection with a retroviral vector harboring the interferon-beta gene.
        Cancer Immunol Immun. 1998; 46: 137-146
        • Natsume A.
        • Mizuno M.
        • Ryuke Y.
        • Yoshida J.
        Antitumor effect and cellular immunity activation by murine interferon-beta gene transfer against intracerebral glioma in mouse.
        Gene Ther. 1999; 6: 1626-1633
        • Fekete E.
        • Ferrigno M.A.
        Studies on a transplantable teratoma of the mouse.
        Cancer Res. 1952; 12: 438-443
        • Berek J.S.
        • Cantrell J.L.
        • Lichtenstein A.K.
        • Hacker N.F.
        • Knox R.M.
        • Nieberg R.K.
        • et al.
        Immunotherapy with biochemically dissociated fractions of Propionibacterium acnes in a murine ovarian cancer model.
        Cancer Res. 1984; 44: 1871-1875
        • Vanhaelen C.P.J.
        • Fisher R.I.
        Requirements for successful immunotherapy and chemoimmunotherapy of a murine model of ovarian cancer.
        Cancer Res. 1981; 41: 980-983
        • Vanhaelen C.P.J.
        • Fisher R.I.
        • Appella E.
        • Ramanathan L.
        Lack of histocompatibility antigens on a murine ovarian teratocarcinoma.
        Cancer Res. 1981; 41: 3186-3191
        • Tochner Z.
        • Mitchell J.B.
        • Harrington F.S.
        • Smith P.
        • Russo D.T.
        • Russo A.
        Treatment of murine intraperitoneal ovarian ascitic tumor with hematoporphyrin derivative and laser light.
        Cancer Res. 1985; 45: 2983-2987
        • Buerk D.G.
        • Riva C.E.
        Vasomotion and spontaneous low frequency oscillations in blood flow and nitric oxide in cat optic nerve head.
        Microvasc Res. 1998; 55: 103-112
        • Buerk D.G.
        • Atochin D.N.
        • Riva C.E.
        Simultaneous tissue Po2, nitric oxide and laser Doppler blood flow measurements during neuronal activation of optic nerve.
        in: Hudetz A. Bruley D. Oxygen transport to tissue XX, advances in experimental medicine and biology. Plenum Press, New York1998: 159-164
        • Gallo-Penn A.M.
        • Shirley P.S.
        • Andrews J.L.
        • Tinlin S.
        • Webster S.
        • Cameron C.
        • et al.
        Systemic delivery of an adenoviral vector encoding canine factor VIII results in short-term phenotypic correction, inhibitor development, and biphasic liver toxicity in hemophilia A dogs.
        Blood. 2001; 97: 107-113
        • Printz M.A.
        • Gonzalez A.M.
        • Cunningham M.
        • Gu D.L.
        • Ong M.
        • Pierce G.F.
        • et al.
        Fibroblast growth factor 2-retargeted adenoviral vectors exhibit a modified biolocalization pattern and display reduced toxicity relative to native adenoviral vectors.
        Hum Gene Ther. 2000; 11: 191-204
        • Yee D.
        • McGuire S.E.
        • Brunner N.
        • Kozelsky T.W.
        • Allred D.C.
        • Chen S.H.
        • et al.
        Adenovirus-mediated gene transfer of herpes simplex virus thymidine kinase in an ascites model of human breast cancer.
        Hum Gene Ther. 1996; 7: 1251-1257
        • Cao G.
        • Su J.
        • Lu W.
        • Zhang F.
        • Zhao G.
        • Marteralli D.
        • et al.
        Adenovirus-mediated interferon-beta gene therapy suppresses growth and metastasis of human prostate cancer in nude mice.
        Cancer Gene Ther. 2001; 8: 497-505
        • Izawa J.I.
        • Sweeney P.
        • Perrotte P.
        • Kedar D.
        • Dong Z.
        • Slaton J.W.
        • et al.
        Inhibition of tumorigenicity and metastasis of human bladder cancer growing in athymic mice by interferon-beta gene therapy results partially from various antiangiogenic affects including endothelial cell apoptosis.
        Clin Cancer Res. 2002; 8: 1258-1270
        • Odaka M.
        • Sterman D.H.
        • Wiewrodt R.
        • Zhang Y.
        • Keifer M.
        • Amin K.M.
        • et al.
        Eradication of intraperitoneal and distant tumor by adenovirus-mediated interferon-beta gene therapy is attributable to induction of systemic immunity.
        Cancer Res. 2001; 61: 6201-6212
        • Odaka M.
        • Rainer W.
        • DeLong P.A.
        • Tanaka T.
        • Zhang Y.
        • Kaiser L.R.
        • et al.
        Analysis of the immunologic response generated by AdIFN-β during successful intraperitoneal tumor gene therapy.
        Mol Ther. 2002; 6: 210-218