Abstract
Newcastle disease virus (NDV), an avian paramyxovirus, has a potential oncolytic effect that may be of significance in the treatment of a variety of cancer diseases. An attenuated lentogenic isolate of NDV (HUJ) demonstrated a selective cytopathic effect upon a panel of human and mouse lung tumor cells, as compared to human nontumorigenic lung cells. The virus-selective oncolytic effect is apoptosis dependent, and related to higher levels of viral transcription, translation and progeny virus formation. Furthermore, NDV-HUJ oncolytic activity is directed in-cis and not through induction of cytokines, that may act in-trans on neighboring cells. Development of primary lung tumors and of the consequent metastasis in mice inoculated with mouse lung tumor cells 3LL-D122 was decreased following treatment with NDV-HUJ. The preferential killing of the tumor cells is not due to a deficiency in the interferon (IFN) system, as expression of the IFN-β gene, in the infected cells, is properly induced. Moreover, pretreatment with IFN effectively protected the tumor cells from the virus oncolytic effect. We conclude therefore, that NDV-HUJ should have a significant benefit in the treatment of lung cancer as well as other malignancies.
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References
Khuri FR, Herbst RS, Fossella FV . Emerging therapies in non-small-cell lung cancer. Ann Oncol 2001; 12: 739–744.
Vora SA, Daly BD, Blaszkowsky L, McGrath JJ, Bankoff M, Supran S et al. High dose radiation therapy and chemotherapy as induction treatment for stage III nonsmall cell lung carcinoma. Cancer 2000; 89: 1946–1952.
Elankumaran S, Rockemann D, Samal SK . Newcastle disease virus exerts oncolysis by both intrinsic and extrinsic caspase-dependent pathways of cell death. J Virol 2006; 80: 7522–7534.
Sinkovics JG, Horvath JC . Newcastle disease virus (NDV): brief history of its oncolytic strains. J Clin Virol 2000; 16: 1–15.
Tzadok-David Y, Metzkin-Eizenberg M, Zakay-Rones Z . The effect of a mesogenic and a lentogenic Newcastle disease virus strain on Burkitt lymphoma Daudi cells. J Cancer Res Clin Oncol 1995; 121: 169–174.
Csatary LK, Eckhardt S, Bukosza I, Czegledi F, Fenyvesi C, Gergely P et al. Attenuated veterinary virus vaccine for the treatment of cancer. Cancer Detect Prev 1993; 17: 619–627.
Csatary LK, Moss RW, Beuth J, Torocsik B, Szeberenyi J, Bakacs T . Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H). Anticancer Res 1999; 19: 635–638.
Freeman AI, Zakay-Rones Z, Gomori JM, Linetsky E, Rasooly L, Greenbaum E et al. Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme. Mol Ther 2006; 13: 221–228.
Schirrmacher V, Haas C, Bonifer R, Ertel C . Virus potentiation of tumor vaccine T-cell stimulatory capacity requires cell surface binding but not infection. Clin Cancer Res 1997; 3: 1135–1148.
Lorence RM, Katubig BB, Reichard KW, Reyes HM, Phuangsab A, Sassetti MD et al. Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy. Cancer Res 1994; 54: 6017–6021.
Schirrmacher V, Ahlert T, Probstle T, Steiner HH, Herold-Mende C, Gerhards R et al. Immunization with virus-modified tumor cells. Semin Oncol 1998; 25: 677–696.
Schirrmacher V, Jurianz K, Roth C, Griesbach A, Bonifer R, Zawatzky R . Tumor stimulator cell modification by infection with Newcastle disease virus: analysis of effects and mechanism in MLTC-CML cultures. Int J Oncol 1999; 14: 205–215.
Lorence RM, Rood PA, Kelley KW . Newcastle disease virus as an antineoplastic agent: induction of tumor necrosis factor-alpha and augmentation of its cytotoxicity. J Natl Cancer Inst 1988; 80: 1305–1312.
Zorn U, Dallmann I, Grosse J, Kirchner H, Poliwoda H, Atzpodien J . Induction of cytokines and cytotoxicity against tumor cells by Newcastle disease virus. Cancer Biother 1994; 9: 225–235.
Krishnamurthy S, Takimoto T, Scroggs RA, Portner A . Differentially regulated interferon response determines the outcome of Newcastle disease virus infection in normal and tumor cell lines. J Virol 2006; 80: 5145–5155.
Stojdl DF, Lichty B, Knowles S, Marius R, Atkins H, Sonenberg N et al. Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat Med 2000; 6: 821–825.
Stojdl DF, Lichty BD, tenOever BR, Paterson JM, Power AT, Knowles S et al. VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. Cancer Cell 2003; 4: 263–275.
Vermeulen K, Van Bockstaele DR, Berneman ZN . Apoptosis: mechanisms and relevance in cancer. Ann Hematol 2005; 84: 627–639.
Weaver BK, Ando O, Kumar KP, Reich NC . Apoptosis is promoted by the dsRNA-activated factor (DRAF1) during viral infection independent of the action of interferon or p53. FASEB J 2001; 15: 501–515.
Bar-Eli N, Giloh H, Schlesinger M, Zakay-Rones Z . Preferential cytotoxic effect of Newcastle disease virus on lymphoma cells. J Cancer Res Clin Oncol 1996; 122: 409–415.
Cheville NF, Beard CW . Cytopathology of Newcastle disease. The influence of bursal and thymic lymphoid systems in the chicken. Lab Invest 1972; 27: 129–143.
Hitchner SB, Johnson EP . A virus of low virulence for immunizing fowls against Newcastle disease (avian pneumoencephalitis). Vet Med 1948; 43: 525–530.
Wagner S, Csatary CM, Gosztonyi G, Koch HC, Hartmann C, Peters O et al. Combined treatment of pediatric high-grade glioma with the oncolytic viral strain MTH-68/H and oral valproic acid. APMIS 2006; 114: 731–743.
Giard DJ, Aaronson SA, Todaro GJ, Arnstein P, Kersey JH, Dosik H et al. In vitro cultivation of human tumors: establishment of cell lines derived from a series of solid tumors. J Natl Cancer Inst 973; 51: 1417–1423.
Jacobs JP, Jones CM, Baille JP . Characteristics of a human diploid cell designated MRC-5. Nature 1970; 227: 168–170.
Machlenkin A, Goldberger O, Tirosh B, Paz A, Volovitz I, Bar-Haim E et al. Combined dendritic cell cryotherapy of tumor induces systemic antimetastatic immunity. Clin Cancer Res 2005; 11: 4955–4961.
Sever JL . Application of a microtechnique to viral serological investigations. J Immunol 1962; 88: 320–329.
Zhou YH, Wu X, Tan F, Shi YX, Glass T, Liu TJ et al. PAX6 suppresses growth of human glioblastoma cells. J Neurooncol 2005; 71: 223–229.
Darash-Yahana M, Pikarsky E, Abramovitch R, Zeira E, Pal B, Karplus R et al. Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis. FASEB J 2004; 18: 1240–1242.
Pitha PM, Kunzi MS . Type I interferon: the ever unfolding story. Curr Top Microbiol Immunol 2007; 316: 41–70.
Darzynkiewicz Z, Bedner E, Smolewski P . Flow cytometry in analysis of cell cycle and apoptosis. Semin Hematol 2001; 38: 179–193.
Hande KR . Etoposide: four decades of development of a topoisomerase II inhibitor. Eur J Cancer 1998; 34: 1514–1521.
Matza-Porges S, Horresh I, Tavor E, Panet A, Honigman A . Expression of an anti apoptotic recombinant short peptide in mammalian cells. Apoptosis 2005; 10: 987–996.
Nagai Y . Paramyxovirus replication and pathogenesis. Reverse genetics transforms understanding. Rev Med Virol 1999; 9: 83–99.
Castagnetta LA, Carruba G . Human prostate cancer: a direct role for oestrogens. Ciba Found Symp 1995; 191: 269–286.
Peeters BP, de Leeuw OS, Koch G, Gielkens AL . Rescue of Newcastle disease virus from cloned cDNA: evidence that cleavability of the fusion protein is a major determinant for virulence. J Virol 1999; 73: 5001–5009.
Romer-Oberdorfer A, Werner O, Veits J, Mebatsion T, Mettenleiter TC . Contribution of the length of the HN protein and the sequence of the F protein cleavage site to Newcastle disease virus pathogenicity. J Gen Virol 2003; 84 (Partt 11): 3121–3129.
Fiola C, Peeters B, Fournier P, Arnold A, Bucur M, Schirrmacher V . Tumor selective replication of Newcastle disease virus: association with defects of tumor cells in antiviral defence. Int J Cancer 2006; 119: 328–338.
Park MS, Garcia-Sastre A, Cros JF, Basler CF, Palese P . Newcastle disease virus V protein is a determinant of host range restriction. J Virol 2003; 77: 9522–9532.
Park MS, Shaw ML, Munoz-Jordan J, Cros JF, Nakaya T, Bouvier N et al. Newcastle disease virus (NDV)-based assay demonstrates interferon-antagonist activity for the NDV V protein and the Nipah virus V, W, and C proteins. J Virol 2003; 77: 1501–1511.
Apostolidis L, Schirrmacher V, Fournier P . Host mediated anti-tumor effect of oncolytic Newcastle disease virus after locoregional application. Int J Oncol 2007; 31: 1009–1019.
Fabian Z, Csatary CM, Szeberenyi J, Csatary LK . p53-Independent endoplasmic reticulum stress-mediated cytotoxicity of a Newcastle disease virus strain in tumor cell lines. J Virol 2007; 81: 2817–2830.
Pecora AL, Rizvi N, Cohen GI, Meropol NJ, Sterman D, Marshall JL et al. Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J Clin Oncol 2002; 20: 2251–2266.
Hotte SJ, Lorence RM, Hirte HW, Polawski SR, Bamat MK, O’Neil JD et al. An optimized clinical regimen for the oncolytic virus PV701. Clin Cancer Res 2007; 13: 977–985.
Kido H, Yokogoshi Y, Sakai K, Tashiro M, Kishino Y, Fukutomi A et al. Isolation and characterization of a novel trypsin-like protease found in rat bronchiolar epithelial Clara cells. A possible activator of the viral fusion glycoprotein. J Biol Chem 1992; 267: 13573–13579.
Stram Y, Shchori D, Chinitch Y, David D, Molad T, Samina I . Molecular characterization of an unassigned Israeli Newcastle disease virus isolate. Avian Dis 1998; 42: 746–751.
Reed LJ, Muench HA . A simple method of estimating fifty percent endpoints. Am J Hyg 1938; 27: 493–497.
Aymard-Henry M, Coleman MT, Dowdle WR, Laver WG, Schild GC, Webster RG . Influenzavirus neuraminidase and neuraminidase-inhibition test procedures. Bull World Health Organ 1973; 48: 199–202.
Luther P, Klett GE, Weber S, Pechmann H, Bergmann KC . The lectin neuraminidase inhibition test: a new method for the detection of antibodies to neuraminidase. J Biol Stand 1983; 11: 115–121.
Gotoh BYF, Ogasawara T, Nagai Y . Isolation of factor Xa from chick embryo as the amniotic endoprotease responsible for paramyxovirus activation. FEBS Lett 1992; 296: 274–278.
Acknowledgements
This work was supported by grant from the Philip Morris US and international external research program and by a grant of the European commission, program number 6. The Cinigene Network of excellence. The ICPI assay was performed by Dr I Samina, The Veterinary Institute, Bet Dagan, Israel.
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Yaacov, B., Elihaoo, E., lazar, I. et al. Selective oncolytic effect of an attenuated Newcastle disease virus (NDV-HUJ) in lung tumors. Cancer Gene Ther 15, 795–807 (2008). https://doi.org/10.1038/cgt.2008.31
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DOI: https://doi.org/10.1038/cgt.2008.31
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