The present work summarizes the research activities on radiation-induced late effects in the rat spinal cord carried out within the “clinical research group ion beam therapy” funded by the German Research Foundation (DFG, KFO 214).
Dose–response curves for the endpoint radiation-induced myelopathy were determined at 6 different positions (LET 16–99 keV/μm) within a 6 cm spread-out Bragg peak using either 1, 2 or 6 fractions of carbon ions. Based on the tolerance dose TD50 of carbon ions and photons, the relative biological effectiveness (RBE) was determined and compared with predictions of the local effect model (LEM I and IV). Within a longitudinal magnetic resonance imaging (MRI)-based study the temporal development of radiation-induced changes in the spinal cord was characterized. To test the protective potential of the ACE (angiotensin converting enzyme)-inhibitor ramipril™, an additional dose–response experiment was performed.
The RBE-values increased with LET and the increase was found to be larger for smaller fractional doses. Benchmarking the RBE-values as predicted by LEM I and LEM IV with the measured data revealed that LEM IV is more accurate in the high-LET, while LEM I is more accurate in the low-LET region. Characterization of the temporal development of radiation-induced changes with MRI demonstrated a shorter latency time for carbon ions, reflected on the histological level by an increased vessel perforation after carbon ion as compared to photon irradiations. For the ACE-inhibitor ramipril™, a mitigative rather than protective effect was found.
This comprehensive study established a large and consistent RBE data base for late effects in the rat spinal cord after carbon ion irradiation which will be further extended in ongoing studies. Using MRI, an extensive characterization of the temporal development of radiation-induced alterations was obtained. The reduced latency time for carbon ions is expected to originate from a dynamic interaction of various complex pathological processes. A dominant observation after carbon ion irradiation was an increase in vessel perforation preferentially in the white matter. To enable a targeted pharmacological intervention more details of the molecular pathways, responsible for the development of radiation-induced myelopathy are required.
Kraft G. Tumor therapy with heavy charged particles. Prog Part Nucl Phys. 2000;45:S473–544. CrossRef
Elsässer T, Weyrather WK, Friedrich T, et al. Quantification of the relative biological effectiveness for ion beam radiotherapy: direct experimental comparison of proton and carbon ion beams and a novel approach for treatment planning. Int J Radiat Oncol Biol Phys. 2010;78(4):1177–83. PubMedCrossRef
Haberer T, Becher W, Schardt D, Kraft G. Magnetic scanning system for heavy ion therapy. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. 1993;330(1):296–305. CrossRef
Okada S, Okeda R, Matsushita S, Kawano A. Immunohistochemical changes of the blood-brain barrier in rat spinal cord after heavy-ion irradiation. Neuropathology. 1998;18(2):188–98. CrossRef
Li YQ, Jay V, Wong CS. Oligodendrocytes in the adult rat spinal cord undergo radiation-induced apoptosis. Cancer Res. 1996;56(23):5417–22. PubMed
Li YQ, Chen P, Haimovitz-Friedman A, Reilly RM, Wong CS. Endothelial apoptosis initiates acute blood–brain barrier disruption after ionizing radiation. Cancer Res. 2003;63(18):5950–6. PubMed
Jenrow KA, Liu J, Brown SL, et al. Combined atorvastatin and ramipril mitigate radiation-induced impairment of dentate gyrus neurogenesis. J Neuro-Oncol. 2011;101(3):449–56. CrossRef
Ryu S, Kolozsvary A, Jenrow KA, Brown SL, Kim JH. Mitigation of radiation-induced optic neuropathy in rats by ACE inhibitor ramipril: importance of ramipril dose and treatment time. J Neuro-Oncol. 2007;82(2):119–24. CrossRef
Nordstrom M, Abrahamsson T, Ervik M, Forshult E, Regardh CG. Central nervous and systemic kinetics of ramipril and ramiprilat in the conscious dog. J Pharmacol Exp Ther. 1993;266(1):147–52. PubMed
- Late normal tissue response in the rat spinal cord after carbon ion irradiation
Christian P. Karger
- BioMed Central
Neu im Fachgebiet Onkologie
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