Abstract
Early oral mucositis occurs in response to accidental upper partial body exposure as well as to radiotherapy in the head-and-neck region. This study was initiated to define the potential of mobilization of endogenous bone marrow (BM) stem cells by rHuG-CSF or of bone marrow transplantation (BMT) to reduce the effect of single-dose irradiation on mouse oral epithelium. A 3 × 3 mm2 area of the lower tongue surface of mice was irradiated with graded single doses (day 0). Mucosal ulceration was used as the endpoint for dose–response analyses. Stem cells were mobilized by rHuG-CSF (8 times/4 days), timed to achieve a maximum of circulating stem cells on days 0, +1, +4, +8 or +10. Alternatively, syngeneic BM was transplanted on these days. The ED50 (dose at which ulceration is expected in 50 % of the animals) for irradiation alone was 11.9 ± 3.4 Gy. Mobilization of stem cells with a maximum of circulating stem cells on days +4, +8 or +10 significantly increased the ED50 to 25.5 ± 10.1, 23.5 ± 10.1 and 26.5 ± 13.0 Gy. In contrast, a maximum of circulating stem cells on day 0 or day +1 had no effect. BMT did not result in a significant change in isoeffective doses in any of the protocols. In conclusion, the response of oral mucosal epithelium to a single-radiation exposure can be significantly reduced by post-exposure mobilization, but not by transplantation, of BM stem cells.
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References
Albert M, Schmidt M, Cordes N, Dörr W (2012) Modulation of radiation induced oral mucositis (mouse) by selective inhibition of β1 integrin. Radiother Oncol 104:230–234. doi:10.1016/j.radonc.2012.06.010
Dörr W (1997) Three A´s of repopulation during fractionated irradiation of squamous epithelia: asymmetry loss, acceleration of stem-cell divisions and abortive divisions. Int J Radiat Biol 72:635–643
Dörr W (2009) Time factors in normal-tissue response to irradiation. In: Joiner M, van der Kogel A (eds) Basic clinical radiobiology, 4th edn. Hodder Arnold, London, pp 149–157
Dörr W, Kummermehr J (1991) Proliferation kinetics of mouse tongue epithelium under normal conditions and following single dose irradiation. Virchows Arch B Cell Pathol Incl Mol Pathol 60:287–294
Dörr W, Kummermehr J (1992) Increased radiation tolerance of mouse tongue epithelium after local conditioning. Int J Radiat Biol 61:369–379
Dörr W, Obeyesekere MN (2001) A mathematical model for cell density and proliferation in squamous epithelium after single-dose irradiation. Int J Radiat Biol 77:497–505. doi:10.1080/09553000010022391
Dörr W, Noack R, Spekl K, Farrell CL (2001) Modification of oral mucositis by keratinocyte growth factor: single radiation exposure. Int J Radiat Biol 77:341–347
Fehrmann A, Dörr W (2005) Effect of EGFR-inhibition on the radiation response of oral mucosa: experimental studies in mouse tongue epithelium. Int J Radiat Biol 81:437–443
Haagen J, Krohn H, Röllig S, Schmidt M, Wolfram K, Dörr W (2009) Effect of selective inhibitors of inflammation on oral mucositis: preclinical studies. Radiother Oncol 92:472–476. doi:10.1016/j.radonc.2009.06.006
Kilic Y, Rajewski K, Dörr W (2007) Effect of post-exposure administration of keratinocyte growth factor (Palifermin) on radiation effects in oral mucosa in mice. Radiat Environ Biophys 46:13–19. doi:10.1007/s00411-006-0079-7
Levesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ (2003) Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest 111:187–196. doi:10.1172/JCI15994
Lombaert IM, Wierenga PK, Kok T, Kampinga HH, deHaan G, Coppes RP (2006) Mobilization of bone marrow stem cells by granulocyte colony-stimulating factor ameliorates radiation-induced damage to salivary glands. Clin Cancer Res 12:1804–1812. doi:10.1158/1078-0432.CCR-05-2381
Pabst S, Spekl K, Dörr W (2004) Changes in the effect of dose fractionation during daily fractionated irradiation: studies in mouse oral mucosa. Int J Radiat Oncol Biol Phys 58:485–492. doi:10.1016/j.ijrobp.2003.09.063
Rankin SM (2012) Chemokines and adult bone marrow stem cells. Immunol Lett 145:47–54. doi:10.1016/j.imlet.2012.04.009
Schmidt M, Haagen J, Noack R, Siegemund A, Gabriel P, Dörr W (2014) Effects of bone marrow or mesenchymal stem cell transplantation on oral mucositis (mouse) induced by fractionated irradiation. Strahlenther Oncol 190:399–404. doi:10.1007/s00066-013-0510-3
Semerad CL, Christopher MJ, Liu F, Short B, Simmons PJ, Winkler I, Levesque JP, Chappel J, Ross FP, Link DC (2005) G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 106:3020–3027. doi:10.1182/blood-2004-01-0272
Sumita Y, Liu Y, Khalili S, Maria OM, Xia D, Key S, Cotrim AP, Mezey E, Tran SD (2011) Bone marrow-derived cells rescue salivary gland function in mice with head and neck irradiation. Int J Biochem Cell Biol 43:80–87. doi:10.1016/j.biocel.2010.09.023
Sunaga H, Fujieda S, Tsuzuki H, Asamoto K, Fukuda M, Saito H (2001) Expression of granulocyte colony-stimulating factor receptor and platelet-derived endothelial cell growth factor in oral and oropharyngeal precancerous lesions. Anticancer Res 21:2901–2906
Acknowledgments
This project was supported by the European Commission, contract number LSHC-CT-2004-503436 (“FIRST”). The authors are grateful to Mrs. D. Pfitzmann and the medical physicists of the Clinic of Radiotherapy and Radiation Oncology at the Medical Faculty C.G. Carus of the Technical University Dresden for skilful assistance.
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Schmidt, M., Piro-Hussong, A., Siegemund, A. et al. Modification of radiation-induced oral mucositis (mouse) by adult stem cell therapy: single-dose irradiation. Radiat Environ Biophys 53, 629–634 (2014). https://doi.org/10.1007/s00411-014-0552-7
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DOI: https://doi.org/10.1007/s00411-014-0552-7