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Radiation Induced Bystander Effect: From in Vitro Studies to Clinical Application

DOI: 10.4236/ijmpcero.2016.51001, PP. 1-17

Keywords: Radiation-Induced Bystander Effect, In Vitro Studies, Preclinical Investigation, Radiotherapy, Immunotherapy, Beneficial Abscopal Effect, Carcinogenic Potential, Secondary Cancers

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In the past 20 years, the classic paradigm in radiobiology recognizing DNA as the main target for the action of radiation has changed. The new paradigm assumes that both targeted and non-targeted effects of radiation determine the final outcome of irradiation. Radiotherapy is one of the main modality treatments of neoplastic diseases with intent to cure, or sometimes to palliate only, thus radiation-induced non-targeted effect, commonly referred to as the radiation-induced bystander effect (RIBE) may have a share in cancer treatment. RIBE is mediated by molecular signaling from radiation targeted cells to their non-irradiated neighbors, and comprises such phenomena as bystander effect, genomic instability, adaptive response and abscopal effect. Whereas first three phenomena may appear both in vitro and in vivo, an abscopal effect is closely related to partial body irradiation and is a systemic effect mediated by immunologic system which synergizes with radiotherapy. From the clinical point of view abscopal effect is particularly interesting due to both its possible valuable contribution to the treatment of metastases, and the potential harmful effects as induction of genetic instability and carcinogenesis. This review summarized the main results of investigations of non-targeted effects coming from in vitro monolayer cultures, 3-dimentional models of tissues, preclinical studies on rodents and clinically observed beneficial abscopal effects with particular emphasis on participation of immunotherapy in the creation of abscopal effects.


[1]  Prise, K.M. and O’Sullivan, J.M. (2009) Radiation-Induced Bystander Signaling in Cancer Therapy. Nature Reviews Cancer, 9, 351-360.
[2]  Rzeszowska-Wolny, J., Przybyszewski, W.M. and Widel, M. (2009) Ionizing Radiation Induced Bystander Effects, Potential Targets for Modulation of Radiotherapy. European Journal of Pharmacology, 625, 156-164.
[3]  Widel, M., Przybyszewski, W.M. and Rzeszowska-Wolny, J. (2009) Radiation-Induced Bystander Effect: The Important Part of Ionizing Radiation Response. Potential Clinical Implications. Postepy Higeny i Medycyny Doswiadczalnej, 63, 377-388.
[4]  Marín, A., Martín, M., Liñán O., Alvarenga, F., López, M., Fernández, L., Büchser, D. and Cerezo, L. (2014) Bystander Effects and Radiotherapy. Reports of Practical Oncology and Radiotherapy, 20, 12-21.
[5]  Iyer, R. and Lehnert, B.E. (2002) Low Dose, Low-LET Ionizing Radiation-Induced Radioadaptation and Associated Early Responses in Unirradiated Cells. Mutation Research, 503, 1-9.
[6]  Chen, S., Zhao, Y., Chiu, S.K., Zhu, L., Wu, L. and Yu, K.N. (2011) Rescue Effects in Radiobiology: Unirradiated Bystander Cells Assist Irradiated Cells through Intercellular Signal Feedback. Mutation Research, 706, 59-64.
[7]  Widel, M., Szurko, A., Przybyszewski, W. and Lanuszewska, J. (2008) Non-irradiated Bystander Fibroblasts Attenuate Damage to Irradiated Cancer Cells. Radioprotection, 43, 194.
[8]  Widel, M., Przybyszewski, W.M., Cieslar-Pobuda, A., Saenko, Y.V. and Rzeszowska-Wolny, J. (2012) Bystander Normal Human Fibroblasts Reduce Damage Response in Radiation Targeted Cancer Cells through Intercellular ROS Level Modulation. Mutation Research, 731, 117-124.
[9]  Mothersill, C. and Seymour, C.B. (2012) Are Epigenetic Mechanisms Involved in Radiation-Induced Bystander Effect? Frontiers in Genetics, 3, 74.
[10]  Mothersill, C. and Seymour, C.B. (1997) Medium from Irradiated Human Epithelial Cells But Not Human Fibroblasts Reduces the Clonogenic Survival of Unirradiated Cells. International Journal of Radiation Biology, 71, 421-427.
[11]  Nagasawa, H. and Little, J.B. (1992) Induction of Sister Chromatid Exchanges by Extremely Low Doses of Alpha-Particles. Cancer Research, 52, 6394-6396.
[12]  Lehnert, B.E., Goodwin, E.H. and Deshpande, A. (1997) Extracellular Factor(s) Following Exposure to Alpha Particles Can Cause Sister Chromatid Exchanges in Normal Human Cells. Cancer Research, 57, 2164-2171.
[13]  Prise, K.M., Belyakov, O.V., Folkard, M. and Michael, B.D. (1998) Studies of Bystander Effects in Human Fibroblasts Using a Charged Particle Microbeam. International Journal of Radiation Biology, 74, 793-798.
[14]  Przybyszewski, W.M., Widel, M., Szurko, A., Lubecka, B., Matulewicz, L., Maniakowski, Z., Polaniak, R., Birkner, E. and Rzeszowska-Wolny, J. (2004) Multiple Bystander Effect of Irradiated Megacolonies of Melanoma Cells on Non-Irradiated Neighbors. Cancer Letters, 214, 91-102.
[15]  Mackonis, E.C., Suchowerska, N., Zhang, M., Ebert, M., McKenzie, D.R. and Jackson, M. (2007) Cellular Response to Modulated Radiation Fields. Physics in Medicine and Biology, 52, 5469-5482.
[16]  Gómez-Millán, J., Katz, I.S., de Araujo Farias, V., Linares-Fernández, J.-L., López-Peñalver, J., Ortiz-Ferrón, G., Ruiz-Ruiz, C., Oliver, F.J. and Ruiz de Almodóvar, J.M. (2012) The Importance of Bystander Effects in Radiation Therapy in Melanoma Skin-Cancer Cells and Umbilical-Cord Stromal Stem Cells. Radiotherapy and Oncology, 102, 450-458.
[17]  Sokolov, M.V. and Neumann, R.D. (2010) Radiation-Induced Bystander Effects in Cultured Human Stem Cells. PLoS One, 5, e14195.
[18]  Liu, Y., Kobayashi, A., Maeda, T., Fu, Q., Oikawa, M., Yang, G., Konishi, T., Uchihori, Y., Hei, T.K. and Wang, Y. (2015) Target Irradiation Induced Bystander Effects between Stem-Like and Non-Stem-Like Cancer Cells. Mutation Research, 773, 43-47.
[19]  Sowa, M.B., Goetz, W., Baulch, J.E., Pyles, D.N., Dziegielewski, J., Yovino, S., Snyder, A.R., de Toledo, S.M., Azzam, E.I. and Morgan, W.F. (2010) Lack of Evidence for Low-LET Radiation Induced Bystander Response in Normal Human Fibroblasts and Colon Carcinoma Cells. International Journal of Radiation Biology, 86, 102-113.
[20]  Widel, M., Lalik, A., Krzywon, A., Poleszczuk, J., Fujarewicz, K. and Rzeszowska-Wolny, J. (2015) The Different Radiation Response and Radiation-Induced Bystander Effects in Colorectal Carcinoma Cells Differing in p53 Status. Mutation Research, 778, 61-70.
[21]  Collado, M., Gil, J., Efeyan, A., Guerra, C., Schuhmacher, A.J, Barradas, M., Benguría, A., Zaballos, A., Flores, J.M., Barbacid, M., Beach, D. and Serrano, M. (2005) Tumour Biology: Senescence in Premalignant Tumours. Nature, 436, 642.
[22]  Davalos, A.R, Coppé, J.-P., Campisi, J. and Desprez, P.-Y. (2010) Senescent Cells as a Source of Inflammatory Factors for Tumor Progression. Cancer and Metastasis Review, 29, 273-283.
[23]  Coppé, J.P., Desprez, P.Y., Krtolica, A. and Campisi, J. (2010) The Senescence Associated Secretory Phenotype: The Dark Side of Tumor Suppression. Annual Review of Pathology, 5, 99-118.
[24]  Pinho, C., Timotin, E., Wong, R., Sur, R.K., Hayward, J.E., Farrell, T.J., Seymour, C. and Mothersill, C. (2015) Assessing Patient Characteristics and Radiation-Induced Non-Targeted Effects in Vivo for High Dose-Rate (HDR) Brachytherapy. International Journal of Radiation Biology, 91, 786-794.
[25]  Pinho, C., Wong, R., Sur, R.K., Hayward, J.E., Farrell, T.J., Seymour, C. and Mothersill, C. (2012) The Involvement of Serum Serotonin Levels Producing Radiation-Induced Bystander Effects for an in Vivo Assay with Fractionated High Dose-Rate (HDR) Brachytherapy. International Journal of Radiation Biology, 88, 791-797.
[26]  Lorimore, S.A., Kadhim, M.A., Pocock, D.A., Papworth, D., Stevens, D.L., Goodhead, D.T. and Wright, E.G. (1998) Chromosomal Instability in the Descendants of Uneradicated Surviving Cells after α-Particle Irradiation. Proceedings of the National Academy of Science of the United States of America, 95, 5730-5733.
[27]  Morgan, W.F. (2003) Non-Targeted and Delayed Effects of Exposure to Ionizing Radiation: II. Radiation-Induced Genomic Instability and Bystander Effects in Vivo, Clastogenic Factors and Transgenerational Effects. Radiation Research, 159, 581-596.[0581:NADEOE]2.0.CO;2
[28]  Morgan, W.F. and Sowa, M.B. (2015) Non-Targeted Effects Induced by Ionizing Radiation: Mechanisms and Potential Impact on Radiation Induced Health Effects. Cancer Letters, 356, 17-21.
[29]  Mendonca, M.S, Kurohara, W., Antoniono, R. and Redpath, J.L. (1998) Plating Efficiency as a Function of Time Postirradiation: Evidence for the Delayed Expression of Lethal Mutations. Radiation Research, 119, 387-393.
[30]  Kadhim, M.A., Lorimore, S.A., Townsend, K.M., Goodhead, D.T., Buckle, V.J. and Wright, E.G. (1995) Radiation Induced Genomic Instability: Delayed Cytogenetic Aberrations and Apoptosis in Primary Human Bone Marrow Cells. International Journal of Radiation Biology, 67, 287-293.
[31]  Marder, B.A. and Morgan, W.F. (1993) Delayed Chromosomal Instability Induced by DNA Damage. Molecular and Cellular Biology, 13, 6667-6677.
[32]  Emerit, I., Quastel, M., Goldsmith, J., Merkin, L., Levy, A., Cernjavski, L., Alaoui-Youssefi, A., Pogossian, A. and Riklis, E. (1997) Clastogenic Factors in the Plasma of Children Exposed at Chernobyl. Mutation Research, 373, 47-54.
[33]  Marozik, P., Mothersill, C., Seymour, C.B., Mosse, I. and Melnov, S. (2007) Bystander Effects Induced by Serum from Survivors of the Chernobyl Accident. Experimantal Hematology, 35, 55-63.
[34]  Marozik, P., Mosse, I., Marozik, M., Melnov, S., Seymour, C. and Mothersil, C. (2015) Non-Targeted Effects of Factors from Blood Serums of Chernobyl Populations. Proceedings of the 3rd International Conference on Radiation and Application in Various Fields of Research, Budva, 8-12 June 2015, 185-190.
[35]  Seymour, C.B. and Mothersill, C. (2000) Relative Contribution of Bystander and Targeted Cell Killing to the Low-Dose Region of the Radiation Dose-Response Curve. Radiation Research, 153, 508-511.[0508:RCOBAT]2.0.CO;2
[36]  Prise, K.M., Folkard, M. and Michael, B.D. (2003) Bystander Responses Induced by Low LET Radiation. Oncogene, 22, 7043-7049.
[37]  Poleszczuk, J., Krzywon, A., Forys, U. and Widel, M. (2015) Connecting Radiation-Induced Bystander Effects and Senescence to Improve Radiation Response Prediction. Radiation Research, 183, 571-577.
[38]  Widel, M. (2011) Intercellular Communication in Response to Radiation Induced Stress: Bystander Effects in Vitro and in Vivo and Their Possible Clinical Implications. In: Singh, N., Ed., Radioisotopes, INTECH, Rijeka, 335-366.
[39]  Mothersill, C. and Seymour, C.B. (2002) Bystander and Delayed Effects after Fractionated Radiation Exposure. Radiation Research, 158, 626-633.[0626:BADEAF]2.0.CO;2
[40]  Soleymanifard, M.T.B., Toossi, R.K. and Mohebbi, S. (2014) Investigation of the Bystander Effect in MRC5 Cells After Acute and Fractionated Irradiation in Vitro. Journal of Medical Physics, 39, 93-97.
[41]  Belyakov, O.V., Mitchell, S.A., Parikh, D., Randers-Pehrson, G., Marino, S.A., Amundson, S.A., Geard, C.R. and Brenner, D.J. (2005) Biological Effects in Unirradiated Human Tissue Induced by Radiation Damage up to 1 mm Away. Proceedings of the National Academy of Science of the United States of America, 102, 14203-14208.
[42]  Sedelnikova, O.A., Nakamura, A., Kovalchuk, O., Koturbash, I., Mitchell, S.A., Marino, S.A., Brenner, D.J. and Bonner, W.M. (2007) DNA Double-Strand Breaks Form in Bystander Cells after Microbeam Irradiation of Three-Dimensional Human Tissue Models. Cancer Research, 67, 4295-4302.
[43]  Belyakov, O.V., Folkard, M., Mothersill, C., Prise, K.M. and Michael, B.D. (2003) A Proliferation-Dependent Bystander Effect in Primary Porcine and Human Urothelial Explants in Response to Targeted Irradiation. British Journal of Cancer, 88, 767-774.
[44]  Konopacka, M., Rogoliński, J. and Slosarek, K. (2011) Bystander Effects Induced by Direct and Scattered Radiation Generated during Penetration of Medium Inside a Water Phantom. Reports of Practical Oncology and Radiotherapy, 16, 256-261.
[45]  Blockhuys, S., Vanhoecke, B., De Wagter, C., Bracke, M. and De Neve, W. (2010) From Clinical Observations of Intensity-Modulated Radiotherapy to Dedicated in Vitro Designs. Mutation Research, 704, 200-205.
[46]  Blyth, B.J. and Sykes, P.J. (2011) Radiation-Induced Bystander Effects: What Are They, and How Relevant Are They to Human Radiation Exposures? Radiation Research, 176, 139-157.
[47]  Siva, S., MacManus, M.P., Martin, R.F. and Martin, O.A. (2015) Abscopal Effects of Radiation Therapy: A Clinical Review for the Radiobiologist. Cancer Letters, 356, 82-90.
[48]  Hatzi, V.I, Laskaratou, D.A., Ifigeneia, V., Mavragani, I.V., Nikitaki, Z., Mangelis, A., Mihalis, I., Panayiotidis, M.I., Pantelias, G.E., Georgia, I., Terzoudi, G.I. and Georgakilas, A.G. (2015) Non-Targeted Radiation Effects in Vivo: A Critical Glance of the Future in Radiobiology. Cancer Letters, 356, 34-42.
[49]  Khan, M.A., Van Dyk, J., Yeung, I.W. and Hill, R.P. (2003) Partial Volume Rat Lung Irradiation; Assessment of Early DNA Damage in Different Lung Regions and Effect of Radical Scavengers. Radiotherapy and Oncology, 66, 95-102.
[50]  Spitz, D.R., Azzam, E.I., Li, J.J. and Gius, D. (2004) Metabolic Oxidation/Reduction Reactions and Cellular Responses to Ionizing Radiation: A Unifying Concept in Stress Response Biology. Cancer Metastasis Reviews, 23, 311-322.
[51]  Koturbash, I., Loree, J., Kutanzi, K., Koganow, C., Pogribny, I. and Kovalchuk, O. (2008) In Vivo Bystander Effect: Cranial X-Irradiation Leads to Elevated DNA Damage, Altered Cellular Proliferation and Apoptosis, and Increased p53 Levels in Shielded Spleen. International Journal of Radiation Oncology, Biology, Physics, 70, 554-562.
[52]  Koturbash, I., Rugo, R.E., Hendricks, C.A., Loree, J., Thibault, B., Kutanzi, K., Pogribny, I., Yanch, J.C., Engelward, B.P. and Kovalchuk, O. (2006) Irradiation Induces DNA Damage and Modulates Epigenetic Effectors in Distant Bystander Tissue in Vivo. Oncogene, 25, 4267-4275.
[53]  Camphausen, K., Moses, M.A., Menard, C., Sproull, M., Beecken, W.D., Folkman, J. and O’Reilly, M.S. (2003) Radiation Abscopal Antitumor Effect Is Mediated through p53. Cancer Research, 63, 1990-1993.
[54]  Koturbash, I., Boyko, A., Rodriguez-Juarez, R., McDonald, R.J., Tryndyak, V.P., Kovalchuk, I., Pogribny, I.P. and Kovalchuk, O. (2007) Role of Epigenetic Effectors in Maintenance of the Long-Term Persistent Bystander Effect in Spleen in Vivo. Carcinogenesis, 28, 1831-1838.
[55]  Ilnytskyy, Y., Koturbash, I. and Kovalchuk, O. (2009) Radiation-Induced Bystander Effects in Vivo Are Epigenetically Regulated in a Tissue-Specific Manner. Environmental and Molecular Mutagenesis, 50, 105-113.
[56]  Koturbash, I., Baker, M., Loree, J., Kutanzi, K., Hudson, D., Pogribny, I., Sedelnikova, O., Bonner, W. and Kovalchuk, O. (2006) Epigenetic Dysregulation Underlies Radiation Induced Transgenerational Genome Instability in Vivo. International Journal of Radiation Oncology, Biology, Physics, 66, 327-330.
[57]  Mancuso, M., Pasquali, E., Leonardi, S., Tanori, M., Rebessi, S., Di Majo, V., Pazzaglia, S., Toni, M.P., Pimpinella, M., Covelli, V. and Saran, A. (2008) Oncogenic Bystander Radiation Effects in Patched Heterozygous Mouse Cerebellum. Proceedings of the National Academy of Science of the United States of America, 105, 12445-12450.
[58]  Demaria, S., Ng, B., Devitt, M.L., Babb, J.S., Kawashima, N., Liebes, L. and Formenti, S.C. (2004) Ionizing Radiation Inhibition of Distant Untreated Tumors (Abscopal Effect) Is Immune Mediated. International Journal of Radiation Oncology, Biology, Physics, 58, 862-870.
[59]  Shiraishi, K., Ishiwata, Y., Nakagawa, K., Yokochi, S., Taruki, C., Akuta, T., Ohtomo, K., Matsushima, K., Tamatani, T. and Kanegasaki, S. (2008) Enhancement of Antitumor Radiation Efficacy and Consistent Induction of the Abscopal Effect in Mice by ECI301, an Active Variant of Macrophage Inflammatory Protein-1Alpha. Clinical Cancer Research, 14, 1159-1166.
[60]  Dewan, M.Z., Galloway, A.E., Kawashima, N., Dewyngaert, J.K., Babb, J.S., Formenti, S.C. and Demaria, S. (2009) Fractionated But Not Single-Dose Radiotherapy Induces an Immune-Mediated Abscopal Effect When Combined with Anti-CTLA-4 Antibody. Clinical Cancer Research, 15, 5379-5388.
[61]  Deng, L., Liang, H., Burnette, B., Beckett, M., Darga, T., Weichselbaum, R.R. and Fu, X.Y. (2014) Irradiation and Anti-PD-L1 Treatment Synergistically Promote Antitumor Immunity in Mice. The Journal of Clinical Investigation, 124, 687-695.
[62]  Hanna, G.G., Coyle, V.M. and Prise, K.M. (2015) Immune Modulation in Advanced Radiotherapies: Targeting Out-of-Field Effects. Cancer Letters, 368, 246-251.
[63]  Reynders, K., Illidge, T., Siva, S., Chang, J.Y. and De Ruysscher, D. (2015) The Abscopal Effect of Local Radiotherapy: Using Immunotherapy to Make a Rare Event Clinically Relevant. Cancer Treatment Reviews, 41, 503-510.
[64]  Kumar, T., Patel, N. and Talwar, A. (2010) Spontaneous Regression of Thoracic Malignancies. Respiratory Medicine, 104, 1543-1550.
[65]  MacManus, M., Harte, R. and Stranex, S. (1994) Spontaneous Regression of Metastatic Renal Cell Carcinoma Following Palliative Irradiation of the Primary Tumour. Irish Journal of Medical Science, 163, 461-463.
[66]  Ohba, K., Omagari, K., Nakamura, T., Ikuno, N., Saeki, S., Matsuo, I., Kinoshita, H., Masuda, J., Hazama, H., Sakamoto, I. and Kohno, S. (1998) Abscopal Regression of Hepatocellular Carcinoma after Radiotherapy for Bone Metastasis. Gut, 43, 575-577.
[67]  Rödel, F., Frey, B., Multhoff, G. and Gaipl U. (2015) Contribution of the Immune System to Bystander and Non-Targeted Effects of Ionizing Radiation. Cancer Letters, 356, 105-113.
[68]  Wersäll, P.J., Blomgren, H., Pisa, P., Lax, I., Kälkner, K.M. and Svedman, C. (2006) Regression of Non-Irradiated Metastases after Extracranial Stereotactic Radiotherapy in Metastatic Renal Cell Carcinoma. Acta Oncologica, 45, 493-497.
[69]  Ishiyama, H., Teh, B.S., Ren, H., Chiang, S., Tann, A., Blanco, A.I., Paulino, A.C. and Amato, R. (2012) Spontaneous Regression of Thoracic Metastases While Progression of Brain Metastases after Stereotactic Radiosurgery and Stereotactic Body Radiotherapy for Metastatic Renal Cell Carcinoma: Abscopal Effect Prevented by the Blood-Brain Barrier? Clinical Genitourinary Cancer, 10, 196-198.
[70]  Golden, E.B., Demaria, S., Schiff, P.B., Chachoua, A. and Formenti, S. (2013) An Abscopal Response to Radiation and Ipilimumab in a Patient with Metastatic Non-Small Cell Lung Cancer. Cancer Immunology Research, 1, 365-372.
[71]  Kachikwu, E.L., Iwamoto, K.S., Liao, Y.P., DeMarco, J.J., Economou, J.S., McBride, W.H. and Schaue, D. (2011) Radiation Enhances Regulatory T Cell Representation. International Journal of Radiation Oncology, Biology, Physics, 81, 1128-1135.
[72]  Garbe, C., Eigentler, T.K., Keilholz, U., Hauschild, A. and Kirkwood, J.M. (2011) Systematic Review of Medical Treatment in Melanoma: Current Status and Future Prospects. The Oncologist, 16, 5-24.
[73]  Silk, A.W., Bassetti, M.F., West, B.T., Tsien, C.I. and Lao, C.D. (2013) Ipilimumab and Radiation Therapy for Melanoma Brain Metastases. Cancer Medicine, 2, 899-906.
[74]  Postow, M.A., Callahan, M.K., Barker, C.A., Yamada, Y., Yuan, J., Kitano, S., Mu, Z., Rasalan, T., Adamow, M., Ritter, E., Sedrak, C., Jungbluth, A.A., Chua, R., Yang, A.S., Roman, R.A., Rosner, S., Benson, B., Allison, J.P., Lesokhin, A.M., Gnjatic, S. and Wolchok, J.D. (2012) Immunologic Correlates of the Abscopal Effect in a Patient with Melanoma. The New England Journal of Medicine, 366, 925-931.
[75]  Grimaldi, A.M., Simeone, E., Giannarelli, D., Muto, P., Falivene, S., Borzillo, V., Giugliano, F.M., Sandomenico, F., Petrillo, A., Curvietto, M., Esposito, A., Paone, M., Palla, M., Palmieri, G., Caracò, C., Ciliberto, G., Mozzillo, N. and Ascierto, P.A. (2014) Abscopal Effects of Radiotherapy on Advanced Melanoma Patients Who Progressed after Ipilimumab Immunotherapy. Oncoimmunology, 3, e28780.
[76]  Thallinger, C., Prager, G., Ringl, H. and Zielinski, C. (2015) Abscopal Effect in the Treatment of Malignant Melanoma. Hautarzt, 66, 545-548.
[77]  Stamell, E.F., Wolchok, J.D., Gnjatic, S., Lee, N.Y. and Brownell, I. (2013) The Abscopal Effect Associated with a Systemic Anti-Melanoma Immune Response. International Journal of Radiation Oncology, Biology, Physics, 85, 293-295.
[78]  Formenti, S.C. and Demaria, S. (2013) Combining Radiotherapy and Cancer Immunotherapy: A Paradigm Shift. Journal of the National Cancer Institute, 105, 256-265.
[79]  Crittenden, M., Kohrt, H., Levy, R., Jones, J., Camphausen, K., Dicker, A., Demaria, S. and Formenti, S. (2015) Current Clinical Trials Testing Combinations of Immunotherapy and Radiation. Seminars in Radiation Oncology, 25, 54-64.
[80]  Stüber, E. and Strober, W. (1996) The T Cell-B Cell Interaction via OX40-OX40L Is Necessary for the T Cell-Dependent Humoral Immune Response. The Journal for Experimental Medicine, 183, 979-989.
[81]  Hirschhorn-Cymerman, D., Rizzuto, G.A., Merghoub, T., Cohen, A.D., Avogadri, F., Lesokhin, A.M., Weinberg, A.D., Wolchok, J.D. and Houghton, A.N. (2009) OX40 Engagement and Chemotherapy Combination Provides Potent Antitumor Immunity with Concomitant Regulatory T Cell Apoptosis. The Journal for Experimental Medicine, 206, 1103-1116.
[82]  Gough, M.J., Crittenden, M.R., Sarff, M., Pang, P., Seung, S.K., Vetto, J.T., Hu, H.M., Redmond, W.L., Holland, J. and Weinberg, A.D. (2010) Adjuvant Therapy with Agonistic Antibodies to CD134 (OX40) Increases Local Control Following Surgical or Radiation Therapy of Cancer in Mice. Journal of Immunotherapy, 33, 798-809.
[83]  Sprung, C.N., Ivashkevich, A., Forrester, H.B., Redon, C.E., Georgakilas, A. and Martin, O.A. (2015) Oxidative DNA Damage Caused by Inflammation May Link to Stress-Induced Non-Targeted Effects. Cancer Letters, 356, 72-81.
[84]  Dong, C., He, M., Tu, W., Konishi, T., Liu, W., Xie, Y., Dang, B., Li, W., Uchihori, Y., Hei, T.K. and Shao, C. (2015) The Differential Role of Human Macrophage in Triggering Secondary Bystander Effects after either Gamma-Ray or Carbon Beam Irradiation. Cancer Letters, 363, 92-100.
[85]  Hendry, J.H. (2001) Genomic Instability: Potential Contributions to Tumour and Normal Tissue Response, and Second Tumours, after Radiotherapy. Radiotherapy and Oncology, 59, 117-126.
[86]  Gamulin, M., Kopjar, N., Grgic, M., Ramic, S., Bisof, V. and Garaj-Vrhovac, V. (2008) Genome Damage in Oropharyngeal Cancer Patients Treated by Radiotherapy. Croatian Medical Journal, 49, 515-527.
[87]  Fucic, A., Gamulin, M., Katic, J., Milic, M., Druzhinin, V. and Grgic, M. (2013) Genome Damage in Testicular Seminoma Patients Seven Years after Radiotherapy. International Journal of Radiation Biology, 89, 928-933.
[88]  Sheridan, J., Tosetto, M., Gorman, J., O’Donoghue, D., Sheahan, K., Hyland, J., Mulcahy, H., Gibbons, D. and O’Sullivan, J. (2013) Effects of Radiation on Levels of DNA Damage in Normal Non-Adjacent Mucosa from Colorectal Cancer Cases. Journal of Gastrointestinal Cancer, 44, 41-45.
[89]  Boice Jr, J.D., Day, N.E., Andersen, A., Brinton, L.A., Brown, R., Choi, N.W., Clarke, E.A., Coleman, M.P., Curtis, R.E., Flannery, J.T., et al. (1985) Second Cancers Following Radiation Treatment for Cervical Cancer: An International Collaboration among Cancer Registries. Journal of the National Cancer Institute, 74, 955-975.
[90]  Brenner, D.J., Curtis, R.E., Hall, E.J. and Ron, E. (2000) Second Malignancies in Prostate Carcinoma Patients after Radiotherapy Compared with Surgery. Cancer, 88, 398-406.<398::AID-CNCR22>3.0.CO;2-V
[91]  Kleinerman, R.A., Boice Jr, J.D., Storm, H.H., Sparen, P., Andersen, A., Pukkala, E., Lynch, C.F., Hankey, B.F. and Flannery, J.T. (1995) Second Primary Cancer after Treatment for Cervical Cancer. An International Cancer Registries Study. Cancer, 76, 442-452.<442::AID-CNCR2820760315>3.0.CO;2-L
[92]  Diallo, I., Haddy, N., Adjadj, E., Samand, A., Quiniou, E., Chavaudra, J., Alziar, I., Perret, N., Guerin, S., Lefkopoulos, D. and de Vathaire, F. (2009) Frequency Distribution of Second Solid Cancer Locations in Relation to the Irradiated Volume among 115 Patients Treated for Childhood Cancer. International Journal of Radiation Oncology, Biology, Physics, 74, 876-883.
[93]  Konopacka, M. and Rzeszowska-Wolny, J. (2001) Antioxidant Vitamins C, E and β-Carotene Reduce DNA Damage before as Well as after ß-Ray Irradiation of Human Lymphocytes in Vitro. Mutation Research, 491, 1-7.


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