Immunosuppression promotes reovirus therapy of colorectal liver metastases
Mortality due to colorectal cancer (CRC) is high and is associated with the development of liver metastases. Approximately 40% of human CRCs harbor an activating mutation in the KRAS oncogene. Tumor cells with activated KRAS are particularly sensitive to Reovirus T3D, a non-pathogenic oncolytic viru...
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Published in | Cancer gene therapy Vol. 13; no. 8; pp. 815 - 818 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
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Nature Publishing Group
01.08.2006
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Abstract | Mortality due to colorectal cancer (CRC) is high and is associated with the development of liver metastases. Approximately 40% of human CRCs harbor an activating mutation in the KRAS oncogene. Tumor cells with activated KRAS are particularly sensitive to Reovirus T3D, a non-pathogenic oncolytic virus. The efficacy of virus-based therapies may be positively or negatively modulated by the host immune system. This study was designed to assess the effect of immunosuppression on Reovirus T3D oncolysis of established colorectal micrometastases in the liver. Mouse C26 CRC cells harbor a mutant Kras gene and are susceptible to Kras-dependent oncolysis by Reovirus T3D in vitro. Isolated C26 liver tumors were established in syngenic immunocompetent BALB/c mice by intrahepatic injection. Reovirus T3D therapy was given as a single intratumoral injection in control mice and in cyclosporin A-treated immunosuppressed mice. Tumor growth was analyzed over time by non-invasive bioluminescence imaging. The outgrowth of established CRC liver metastases in immunocompetent mice was efficiently but temporarily inhibited with a single injection of Reovirus T3D. Immunosuppression with cyclosporin A markedly increased and prolonged the therapeutic effect and allowed complete Reovirus T3D-induced tumor eradication in a subpopulation of the mice. We conclude that Reovirus T3D is an effective therapeutic agent against established C26 colorectal liver metastases and that immunosuppression enhances treatment efficacy. Cancer Gene Therapy (2006) 13, 815-818. doi:10.1038/sj.cgt.7700949; published online 10 March 2006. |
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AbstractList | Mortality due to colorectal cancer (CRC) is high and is associated with the development of liver metastases. Approximately 40% of human CRCs harbor an activating mutation in the KRAS oncogene. Tumor cells with activated KRAS are particularly sensitive to Reovirus T3D, a non-pathogenic oncolytic virus. The efficacy of virus-based therapies may be positively or negatively modulated by the host immune system. This study was designed to assess the effect of immunosuppression on Reovirus T3D oncolysis of established colorectal micrometastases in the liver. Mouse C26 CRC cells harbor a mutant Kras gene and are susceptible to Kras-dependent oncolysis by Reovirus T3D in vitro. Isolated C26 liver tumors were established in syngenic immunocompetent BALB/c mice by intrahepatic injection. Reovirus T3D therapy was given as a single intratumoral injection in control mice and in cyclosporin A-treated immunosuppressed mice. Tumor growth was analyzed over time by non-invasive bioluminescence imaging. The outgrowth of established CRC liver metastases in immunocompetent mice was efficiently but temporarily inhibited with a single injection of Reovirus T3D. Immunosuppression with cyclosporin A markedly increased and prolonged the therapeutic effect and allowed complete Reovirus T3D-induced tumor eradication in a subpopulation of the mice. We conclude that Reovirus T3D is an effective therapeutic agent against established C26 colorectal liver metastases and that immunosuppression enhances treatment efficacy. Mortality due to colorectal cancer (CRC) is high and is associated with the development of liver metastases. Approximately 40% of human CRCs harbor an activating mutation in the KRAS oncogene. Tumor cells with activated KRAS are particularly sensitive to Reovirus T3D, a non-pathogenic oncolytic virus. The efficacy of virus-based therapies may be positively or negatively modulated by the host immune system. This study was designed to assess the effect of immunosuppression on Reovirus T3D oncolysis of established colorectal micrometastases in the liver. Mouse C26 CRC cells harbor a mutant Kras gene and are susceptible to Kras-dependent oncolysis by Reovirus T3D in vitro. Isolated C26 liver tumors were established in syngenic immunocompetent BALB/c mice by intrahepatic injection. Reovirus T3D therapy was given as a single intratumoral injection in control mice and in cyclosporin A-treated immunosuppressed mice. Tumor growth was analyzed over time by non-invasive bioluminescence imaging. The outgrowth of established CRC liver metastases in immunocompetent mice was efficiently but temporarily inhibited with a single injection of Reovirus T3D. Immunosuppression with cyclosporin A markedly increased and prolonged the therapeutic effect and allowed complete Reovirus T3D-induced tumor eradication in a subpopulation of the mice. We conclude that Reovirus T3D is an effective therapeutic agent against established C26 colorectal liver metastases and that immunosuppression enhances treatment efficacy. Cancer Gene Therapy (2006) 13, 815-818. doi:10.1038/sj.cgt.7700949; published online 10 March 2006. |
Audience | Academic |
Author | Borel Rinkes, I H M Kranenburg, O Smakman, N van den Wollenberg, D J M van der Bilt, J D W Hoeben, R C |
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BackLink | https://www.ncbi.nlm.nih.gov/pubmed/16543920$$D View this record in MEDLINE/PubMed |
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CitedBy_id | crossref_primary_10_1038_cddis_2013_259 crossref_primary_10_1128_JVI_00304_12 crossref_primary_10_1158_1078_0432_CCR_08_0524 crossref_primary_10_1089_hum_2014_092 crossref_primary_10_1016_j_critrevonc_2018_07_011 crossref_primary_10_1517_14712590903307370 crossref_primary_10_1016_j_canlet_2007_02_002 crossref_primary_10_1158_1078_0432_CCR_09_0796 crossref_primary_10_5662_wjm_v6_i1_25 crossref_primary_10_1245_s10434_007_9557_7 crossref_primary_10_1038_sj_cgt_7701068 crossref_primary_10_1093_jnci_djm229 crossref_primary_10_1038_onc_2011_478 crossref_primary_10_1016_j_ymeth_2010_08_011 crossref_primary_10_1158_1078_0432_CCR_10_2848 crossref_primary_10_1038_mt_2008_162 crossref_primary_10_3390_cancers12113219 crossref_primary_10_1517_14712590903002039 crossref_primary_10_1002_ijc_22758 crossref_primary_10_4137_CMO_S416 crossref_primary_10_3390_v8010004 crossref_primary_10_1038_cgt_2008_2 crossref_primary_10_1007_s10637_015_0216_8 crossref_primary_10_3389_fonc_2014_00145 crossref_primary_10_1111_j_1751_7915_2011_00296_x crossref_primary_10_1089_hum_2009_135 crossref_primary_10_1016_j_nec_2020_12_008 crossref_primary_10_1517_13543780802533401 crossref_primary_10_1039_B917597K crossref_primary_10_1158_0008_5472_CAN_14_3761 crossref_primary_10_1002_pbc_25464 crossref_primary_10_1158_1078_0432_CCR_10_2159 crossref_primary_10_4236_jct_2013_46127 |
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References | Coffey, MC, Strong, JE, Forsyth, PA, Lee, PW 1998; 282 Andreyev, HJ, Norman, AR, Cunningham, D, Oates, JR, Clarke, PA 1998; 90 Everts, B, van der Poel, HG 2005; 12 Smakman, N, Martens, A, Kranenburg, O, Borel Rinkes, IH 2004; 122 Yang, WQ, Lun, X, Palmer, CA, Wilcox, ME, Muzik, H, Shi, ZQ 2004; 10 Norman, KL, Lee, PW 2005; 10 Loken, SD, Norman, K, Hirasawa, K, Nodwell, M, Lester, WM, Demetrick, DJ 2004; 3 Hirasawa, K, Nishikawa, SG, Norman, KL, Coffey, MC, Thompson, BG, Yoon, CS 2003; 63 Forrest, JC, Dermody, TS 2003; 77 Smakman, N, van den Wollenberg, JM, Borel Rinkes, IHM, Hoeben, RC, Kranenburg, O 2005; 79 KL Norman (BF7700949_CR7) 2005; 10 HJ Andreyev (BF7700949_CR5) 1998; 90 B Everts (BF7700949_CR1) 2005; 12 MC Coffey (BF7700949_CR3) 1998; 282 WQ Yang (BF7700949_CR6) 2004; 10 N Smakman (BF7700949_CR9) 2004; 122 SD Loken (BF7700949_CR10) 2004; 3 K Hirasawa (BF7700949_CR8) 2003; 63 JC Forrest (BF7700949_CR2) 2003; 77 N Smakman (BF7700949_CR4) 2005; 79 |
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SubjectTerms | Animals Bioluminescence Care and treatment Cell Line, Tumor Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - immunology Colorectal Neoplasms - pathology Colorectal Neoplasms - therapy Combined Modality Therapy Cyclosporin A Cyclosporine - pharmacology Diagnosis Gene therapy Genetic aspects Health aspects Hepatocytes Immune system Immunocompetence Immunosuppression Immunosuppressive Agents - pharmacology Injection Injections, Intralesional Liver Liver Neoplasms - immunology Liver Neoplasms - secondary Liver Neoplasms - therapy Mammalian orthoreovirus 3 Metastases Metastasis Methods Mice Mice, Inbred BALB C Mutation Oncolysis Oncolytic Virotherapy Oncolytic Viruses Physiological aspects Reovirus Risk factors Transplantation, Isogeneic Tumor cells Xenograft Model Antitumor Assays |
Title | Immunosuppression promotes reovirus therapy of colorectal liver metastases |
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