Influence of Local Temporary Ischemia on Radiotherapy Effects


Here we summarize and discuss the body of information concerning mechanisms and regulation of local short-duration preconditioning that may accompany experimental radiation therapy. Based on the results of our previous studies in vivo we investigated possible impact of local temporary ischemia on the effectiveness of ionizing radiation-based anti-cancer therapy. We used total body-irradiated or abdomen only-irradiated healthy rats. Chosen blood parameters, changes in bone marrow cytological picture as well as histological picture of the small intestine were used as toxicity markers. We found a significant transient modification in lipid peroxides, triglycerides, uric acid concentration, SOD isoenzymes activity in the rat serum, increased numbers of small intestine crypts and suppression of bone marrow polychromatic erythrocytes and polychromatic erythrocytes with micronuclei. No significant differences were observed in MnSOD isoenzyme activity in serum and in small intestine homogenates after local temporary ischemia, nor after irradiation, nor combined treatment. Some differences were observed in intestinal tissue CuZnSOD activities. Nevertheless, great variations in response to ischemia, radiation or combined treatment was noted concerning this parameter. Histological picture of the small intestine from ionizing radiation-treated rats has indicated a marked protection of crypt survival by local temporary ischemic preconditioning. Some of the ionizing radiation-caused toxic effects were reduced in animals treated with local ischemic preconditioning. Together, these results provide a new insight into development of a more effective anticancer therapy combining short-duration ischemia and ionizing radiation modality.

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P. Walichiewicz, A. Sochanik and W. Przybyszewski, "Influence of Local Temporary Ischemia on Radiotherapy Effects," Journal of Cancer Therapy, Vol. 2 No. 2, 2011, pp. 209-216. doi: 10.4236/jct.2011.22027.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] H. R. Withers and L. J. Peters, “Biological Aspects of Radiation Therapy,” In: G. H. Fletcher, 3rd Edition, Textbook of Radiotherapy, Lea & Febiger, Inc., Philadelphia, 1980, pp. 103-180.
[2] H. R. Withers, “The Four R’s of Radiotherapy,” In: J. T. Lett, H. Adler, Ed., Advances in Radiation Biology, Academic Press, New York, 1975, pp. 241-247.
[3] G. G. Steel, T. J McMillan and J. H. Peacock, “The 5 R’s of Radiobiology,” International Journal of Radiation Biology, Vol. 56, No. 6, 1989, pp. 1045-1048. doi:10.1080/09553008914552491
[4] J. H. Kaanders, L. A. Pop, H. A. Marres, J. Liefers, F. J. van den Hoogen, W. A. van Daal and A. J. van der Kogel, “Accelerated Radiotherapy with Carbogen and Nicotinamide (ARCON) for Laryngeal Cancer,” Radiotherapy & Oncology, Vol. 48, No. 2, 1998, pp. 115-122. doi:10.1016/S0167-8140(98)00043-7
[5] A. T. Gage and P. K. Stanton, “Hypoxia Triggers Neuroprotective Alterations in Hippocampal Gene Expression via a Heme-Containing Sensor,” Brain Research, Vol. 719, No. 1-2, 1996, pp. 172-178. doi:10.1016/0006-8993(96)00092-3
[6] F. C. Barone, R. F. White, P. A. Spera, J. Ellison, R. W. Currie, X. Wang and G. Z. Feuerstein, “Ischemic Preconditioning and Brain Tolerance: Temporal Histological and Functional Outcomes, Protein Synthesis Requirement, and Interleukin-1 Receptor Antagonist and Early Gene Expression,” Stroke, Vol. 29, No. 9, 1998, pp. 1937-1950. doi:10.1161/01.STR.29.9.1937
[7] J. F. Ward, J. R. Milligan and J. R. Fahey, “Factors Controlling the Radiosensitivity of Cellular DNA,” In: D. T. Goodhead, P. O’Neil and H. G. Menzel, Eds., Microdosimettry—An Interdyscyplinary Approach, The Royal Society of Chemistry, 1997, pp. 57-64.
[8] D. Poppek and T. Grune, “Proteasomal Defense of Oxidative Protein Modifications,” Antioxidants & Redox Signaling, Vol. 8, No. 1-2, 2006, pp. 173-184. doi:10.1089/ars.2006.8.173
[9] M. Valko, D. Leibfritz, J. Moncol, M. T. Cronin, M. Mazur and J. Telser, “Free Radicals and Antioxidants in Normal Physiological Functions and Human Disease,” The International Journal of Biochemistry & Cell Biology, Vol. 39, No. 1, 2007, pp. 44-84. doi:10.1016/j.biocel.2006.07.001
[10] C.-R. Wang, J. Nguyen and Q.-B Lu, “Bond Breaks of Nucleotides by Dissociative Electron Transfer of Nonequilibrium Prehydrated Electrons: A New Molecular Mechanism for Reductive DNA Damage,” Journal of the American Chemical Society, Vol. 131, No. 32, 2009, pp. 11320-11322. doi:10.1021/ja902675g
[11] Q. B. Lu, S. Kalantari and C. R Wang, “Electron Transfer Reaction Mechanism of Cisplatin with DNA at the Molecular Level,” Molecular Pharmacology, Vol. 4, No. 4, 2007, pp. 624-628. doi:10.1021/mp070040a
[12] Y. Zheng, D. J. Hunting, P. Avotte and L. Sanche, “Role of Secondary Low-Energy Electrons in the Concomitant Chemoradiation Therapy of Cancer,” Physical Review Letters, Vol. 100, No. 19, 2008, Article ID 198101. doi:10.1103/PhysRevLett.100.198101
[13] P. Dent, A. Yacoub, J. Contessa, R. Carron, G. Amorino, K. Valerie, M. P. Hagan, S. Grant, R. Schmidt-Ullrich, “Stress and Radiation-Induced Activation of Multiple Intracellular Signaling Pathways,” Radiation Research, Vol. 159, No. 3, 2003, pp. 283-300. doi:10.1667/0033-7587(2003)159[0283:SARIAO]2.0.CO;2
[14] A. Negre-Salvayre, C. Coatrieux, C. Ingueneau and R. Salvayre, “Advanced Lipid Peroxidation End Products in Oxidative Damage to Proteins. Potential Role in Diseases and Therapeutic Prospects for the Inhibitors,” British Journal of Pharmacology, Vol. 153, No. 1, 2008, pp. 6-20. doi:10.1038/sj.bjp.0707395
[15] P. Walichiewicz, W. M. Przybyszewski, J. Jochem, M. Widel and A. Koterbicka, “Inhibitory Effect of Local Ischemic Preconditioning on Gamma Ray-Induced Lipid Peroxidation in Rats: A Preliminary Study,” International Journal of Tissue Reactions, Vol. 24, No. 4, 2002, pp. 143-150.
[16] P. Walichiewicz, W. M. Przybyszewski, J. Jochem, M. Widel, A. Koterbicka and M. Snietura, “Inhibitory Effect of Local Ischaemic Preconditioning in Total Body Irradiated Rats,” Carcinogens, Mutagens and Teratogens, Vol. 23, No. 1 (Supplement), 2003, pp. 195-205. doi:10.1002/tcm.10074
[17] P. Walichiewicz, W. M. Przybyszewski, M. Snietura, D. Lange, A. Bkhiyan and M. Widel, “Protective Effect of Local Temporary Ischemia Depends on Applied Dose of Radiation,” Cancer Letters, Vol. 222, No. 1, 2005, pp. 113-118. doi:10.1016/j.canlet.2004.09.006
[18] W. M. Przybyszewski, P. Walichiewicz, M. Widel, R. Polaniak, M. Snietura, Z. Maniakowski and W. Jachec, “Influence of Local Peripheral Temporary Ischemia on Biochemical and Histological Effects in Small Intestine and Serum of Rats Following Abdominal Irradiation,” Folia Biologica (Praha), Vol. 54, No. 6, 2008, pp. 169-176.
[19] D. W. Reif, J. Schubert and S. D. Aust, “Iron Release from Ferritin and Lipid Peroxidation by Radiolytically Generated Reducing Radicals,” Archives of Biochemistry and Biophysics, Vol. 264, No. 1, 1988, pp. 238-243. doi:10.1016/0003-9861(88)90590-5
[20] A. M. Almeida, C. R. A. Bertoncini, J. Borecky, N. C. Souza-Pinto and A. E. Vercesi, “Mitochondrial DNA Damage Associated with Lipid Peroxidation of the Mitochondrial Membrane Induced by Fe+2 -Citrate,” Annais de Academia Brasileira de Ciencias, Vol. 78, No. 3, 2006, pp. 505-514. doi: 10.1590/s0001-37652006000300010.
[21] D. R. Spitz, E. I. Azzam, J. J. Li and D. Gius, “Metabolic Oxidation/Reduction Reactions and Cellular Responses to Ionizing Radiation: A Unifying Concept in Stress Response Biology,” Cancer and Metastasis Reviews, Vol. 23, No. 3-4, 2004, pp. 311-322. doi:10.1023/B:CANC.0000031769.14728.bc
[22] S. Motoori, H. J. Majima, M. Ebara, H. Kato, F. Hirai, S. Kakinuma, C. Yamaguchi, T. Ozawa, T. Nagano, H. Tsujii and H. Saisho, “Overexpression of Mitochondrial Manganese Superoxide Dismutase Protects against Radiation-Induced Cell Death in the Human Hepatocellular Carcinoma Cell Line HLE,” Cancer Research, Vol. 61, No. 14, 2001, pp. 5382-5388.
[23] E. Ueta, K. Yoneda, T. Kimura, Y. Tatemoto, S. Doi, T. Yamamoto and T. Osaki, “Mn-SOD Antisense Upregulates in vivo Apoptosis of Squamos Cell Carcinoma Cells by Anticancer Drugs and Gamma-Rays Regulating Expression of the BCL-2 Family Proteins COX-2 and p21,” International Journal of Cancer, Vol. 94, No. 4, 2001, pp. 545-550. doi:10.1002/ijc.1513
[24] G. Guo, Y. Yan-Sanders, B. D. Lyn-Cook, T. Wang, D. Tamae, J. Ogi, A. Khaletskiy, Z. Li, C. Weydert, J. A. Longmate, T. T. Huang, D. R. Spitz, L. W. Oberley and J. J. Li, “Manganese Superoxide Dismutase-Mediated Gene Expression in Radiation-Induced Adaptive Responses,” Molecular and Cellular Biology, Vol. 23, No. 7, 2003, pp. 2362-2378. doi:10.1128/MCB.23.7.2362-2378.2003
[25] R. M. J. Palmer, A. G. Ferrige and S. Moncada, “Nitric Oxide Release Accounts for the Biological Activity of Endothelium-Derived Relaxing Factor,” Nature, Vol. 327, No. 6122, 1987, pp. 524-526. doi:10.1038/327524a0
[26] C. E. Murry, R. B. Jennings and K. A. Reimer, “New Insight into Potential Mechanisms of Ischemic Preconditioning,” Circulation, Vol. 84, No. 1, 1991, pp. 442-445.
[27] H. Rubbo, V. Darley-Usmar and B. A. Freeman, “Nitric Oxide Regulation of Tissue Free Radical Injury,” Chemical Research in Toxicology, Vol. 9, No. 5, 1996, pp. 809-820. doi:10.1021/tx960037q
[28] J. Liebmann, A. M. deLuca, D. Coffin, L. K. Keefer, D. Venzon, D. A. Wink and J. B. Mitchell, “In Vivo Radiation Protection by Nitric Oxide Modulation,” Cancer Research, Vol. 54, No. 13, 1994, pp. 3365-3368.
[29] C. E. Murry, R. B. Jennings and K. A. Reimer, “Preconditioning with Ischemia: A Delay of Lethal Cell Injury in Ischemic Myocardium,” Circulation, Vol. 74, No. 5, 1986, pp. 1124-1136. doi:10.1161/01.CIR.74.5.1124
[30] C. J. Pang, R. Z. Yang, A. Zhong, N. Xu, B. Boyd and C. R. Forrest, “Acute Ischaemic Preconditioning Protects against Skeletal Muscle Infarction in the Pig,” Cardiovascular Research, Vol. 29, No. 6, 1995, pp. 782-786.
[31] C. A. Schroeder Jr., H. T. Lee, P. M. Shah, S. C. Babu, C. L. Thompson and F. L. Belloni, “Preconditioning with Ischaemia or Adenosine Protects Skeletal Muscle from Ischaemic Tissue Reperfusion Injury,” Journal of Surgical Research, Vol. 63, No. 1, 1996, pp. 29-34. doi:10.1006/jsre.1996.0217
[32] K. J. Hardy, D. N. McClure and S. Subwonqcharoen, “Ischaemic Preconditioning of the Liver: A Preliminary Study,” ANZ Journal of Surgery, Vol. 66, No. 10, 1996, pp. 707-710. doi:10.1111/j.1445-2197.1996.tb00722.x
[33] K. Matsushita and A. M. Hakim, “Transient Forebrain Ischaemia Protects against Subsequent Focal Cerebral Ischaemia witout Changing Cerebral Perfusion,” Stroke, Vol. 26, No. 6, 1995, pp. 1047-1052. doi:10.1161/01.STR.26.6.1047
[34] T. Tsuruma, A. Yagihashi, T. Matsuno, X. M. Zou, K. Asanuma, K. Sasaki and K. Hirata, “Induction of Warm Ischaemic Tolerance Following Preconditioning of the Small Intestine,” Transplantation Proceedings, Vol. 28, No. 3, 1996, pp. 1298-1299.
[35] C. F. Islam, R. T. Mathie, M. D. Dinneen, E. A. Kiely, A. M. Peters and P. A. Grace, “Ischaemia-Reperfusion Injury in the Rat Kidney: The Effect of Preconditioning,” British Journal of Urology International, Vol. 79, No. 6, 1997, pp. 842-847.
[36] B. C. Gho, R. G. Shoemaker, M. A. van den Doel, D. J. Duncker and P. D. Verdouw, “Myocardial Protection by Brief Ischaemia in Non-Cardiac Tissue,” Circulation, Vol. 94, No. 9, 1996, pp. 2193-2200.
[37] S. Moncada and E. A Higgs, “Endogenous Nitric Oxide: Physiology, Pathology and Clinical Relevance,” European Journal of Clinical Investigation, Vol. 21, No. 4, 1991, pp. 361-374. doi:10.1111/j.1365-2362.1991.tb01383.x
[38] J. R. Parratt, “Protection of the Heart by Ischaemic Preconditioning Mechanisms and Possibilities for Pharmacological Exploitation,” Trends in Pharmacological Sciences, Vol. 15, No. 1, 1994, pp. 19-25. doi:10.1016/0165-6147(94)90129-5
[39] D. M. Yellon, G. F. Baxter, D. Garcia-Dorado, G. Heusch and M. S. Sumeray, “Ischemic Preconditioning: Present Position and Future Directions,” Cardiovascular Research, Vol. 37, No. 1, 1998, pp. 21-33. doi:10.1016/S0008-6363(97)00214-9
[40] R. J. Schauer, A. L. Gerbes, D. Vonier, M. op den Winkel, P. Fraunberger and M. Bilzer, “Induction of Cellular Resistance against Kupffer Cell-Derived Oxidant Stress: A Novel Concept of Hepatoprotection by Ischemic Preconditioning,” Hepatology, Vol. 37, No. 2, 2003, pp. 286-295. doi:10.1053/jhep.2003.50064
[41] C. Peralta, L. Fernandez, J. Panes, N. Prats, M. Sans, J. M. Pique, E. Gelpi and J. Rosello-Catafau, “Preconditioning Protects against Systemic Disorders Associated with Hepatic Ischemia-Reperfusion through Blockade of Tumor Necrosis Factor-Induced P-Selectin Up-Regulation in the Rat,” Hepatology, Vol. 33, No. 1, 2001, pp. 100-113. doi:10.1053/jhep.2001.20529
[42] R. Carini, M. G. De Cesaris, R. Splendore, M. Bagnati and E. Albano, “Ischemic Preconditioning Reduces Na(+) Accumulation and Cell Killing in Isolated Rat Hepatocytes Exposed to Hypoxia,” Hepatology, Vol. 31, No. 1, 2000, pp. 166-172. doi:10.1002/hep.510310125
[43] L. Fernandez, N. Heredia, L. Grande, G. Gomez, A. Rimola, A. Marco, E. Gelpi, J. Rosello-Catafau and C. Peralta, “Preconditioning Protects Liver and Lung Damage in Rat Liver Transplantation: Role of Xanthine/Xanthine Oxidase,” Hepatology, Vol. 36, No. 3, 2002, pp. 562-572. doi:10.1053/jhep.2002.34616
[44] M. Suzuki, N. Sasaki, T. Miki, N. Sakamoto, Y. Ohmoto-Sekine, M. Tamagawa, S. Seino, E. Marban and H. Nakaya, “Role of Sarcolemmal K(ATP) Channels in Cardioprotection against Ischemia/Reperfusion Injury in Mice,” Journal of Clinical Investigation, Vol. 109, No. 4, 2002, pp. 509-516.
[45] B. Wu, A. Ootani, R. Iwakiri, T. Fujise, S. Tsunada, S. Toda and K. Fujimoto, “Ischemic Preconditioning Attenuates Ischemia-Reperfusion-Induced Mucosal Apoptosis by Inhibiting the Mitochondrial-Dependent Pathway in Rat Small Intestine,” American Journal of Physiology-Gastrointestinal and Liver Physiology, Vol. 286, No. 4, 2004, pp. G580-587. doi:10.1152/ajpgi.00335.2003
[46] L. E. Feinendegen, “Reactive Oxygen Species in Cell Responses to Toxic Agents,” Human & Experimental Toxicology, Vol. 21, No. 2, 2002, pp. 85-90. doi:10.1191/0960327102ht216oa
[47] W. Chen, S. Gabel, C. Steenbergen and E. Murphy, “A Redox-Based Mechanism for Cardioprotection Induced by Ischemic Preconditioning in Perfused Rat Heart,” Circulation Research, Vol. 77, No. 2, 1995, pp. 424-429.
[48] A. Skyschally, R. Schulz, P. Gres, H. G. Korth and G. Heusch, “Attenuation of Ischemic Preconditioning in Pigs by Scavenging of Free Oxyradicals with Ascorbic Acid,” American Journal of Physiology - Heart and Circulatory Physiology, Vol. 284, No. 2, 2003, pp. H698-703.
[49] B. Hassel, A. Ilebekk and T. Tonnessen, “Cardiac Accumulation of Citrate during Brief Myocardial Ischaemia and Reperfusion in the Pig in vivo,” Acta Physiologica Scandinavica, Vol. 164, No. 1, 1998, pp. 53-59. doi:10.1046/j.1365-201X.1998.0400e.x
[50] M. Kojima, R. Iwakiri, B. Wu, T. Fujise, K. Watanabe, T. Lin, S. Amemori, H. Sakata, R. Shimoda, T. Oguzu, A. Ootani, S. Tsunada and K. Fujimoto, “Effects of Antioxi- dative Agents on Apoptosis Induced by Ischaemia- Reperfusion in Rat Intestinal Mucosa,” Alimentary Pharmacology & Therapeutics, Vol. 18, No. 1 (Supplement), 2003, pp. 139-145. doi:10.1046/j.1365-2036.18.s1.16.x
[51] F. Yamakura, H. Taka, T. Fujimura and K. Murayama, “Inactivation of Human Manganese-Superoxide Dismutase by Peroxynitrite is Caused by Exclusive Nitration of Tyrosine 34 to 3-Nitrotyrosine” The Journal of Biological Chemistry, Vol. 273, No. 23, 1998, pp. 14085-14089. doi:10.1074/jbc.273.23.14085
[52] L. A Macmillan-Crow and D. L. Cruthirds, “Invited Review: Manganese Superoxide Dismutase in Disease,” Free Radical Research, Vol. 34, No. 4, 2001, pp. 325-336. doi:10.1080/10715760100300281
[53] M. Maczewski, M. Duda, W. Pawlak and A. Beresewicz, “Endothelial Protection from Reperfusion Injury by Ischemic Preconditioning and Diazoxide Involves a SOD-Like Anti-O2-Mechanism,” Journal of Physiology and Pharmacology, Vol. 55, No. 3, 2004, pp. 537-550.
[54] M. Valko, C. J Rhodes, J. Moncol, M. Izakovic and M. Mazur, “Free Radicals, Metals and Antioxidants in Oxidative Stress-Induced Cancer,” Chemico-Biological Interactions, Vol. 160, No. 1, 2006, pp. 1-40. doi:10.1016/j.cbi.2005.12.009
[55] S. Islekel, H. Islekel, G. Gruner and N. Ozdamar, “Alterations in Superoxide Dismutase, Glutathione Peroxidase and Catalase Activities in Experimental Cerebral Ischemia-Reperfusion,” Research in Experimental Medicine, Vol. 199, No. 3, 1999, pp. 167-176. doi:10.1007/s004330050121
[56] W. Zhang, Q. He, L. L. Chan, F. Zhou, M. El Naghy, E. B. Thompson and N. H. Ansari, “Involvement of Caspases in 4-Hydroxy-Alkenal-Induced Apoptosis in Human Leukemic Cells,” Free Radical Biology and Medicine, Vol. 30, No. 6, 2001, pp. 699-700. doi:10.1016/S0891-5849(01)00465-8
[57] O. Hahn, A. Szijarto, G. Lotz, Z. Schaff, Z. Viqvary, L. Vali and P. K. Kupcsulik, “The Effect of Ischemic Preconditioning Prior to Intraoperative Radiotherapy on Ischemic and on Reperfused Rat Liver,” Journal of Surgical Research, Vol. 142, No. 1, 2007, pp. 32-44. doi:10.1016/j.jss.2006.10.026

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