Late normal tissue response in the rat spinal cord after carbon ion irradiation

Abstract

Background: 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).

Methods and materials: 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.

Results: 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.

Conclusions: 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.

Keywords: Carbon ion therapy; Magnetic resonance imaging; Radiation induced myelopathy; Rat spinal cord; Relative biological effectiveness (RBE).

Fig. 1

Dose–response curves for the endpoint paresis grade II after irradiation of the spinal cord with either single (a) or split (b) doses of carbon ions or photons at 6 different positions within a 6 cm SOBP

Fig. 2

RBE-dependence on LET for single and split doses. In addition, RBE-values predicted by LEM I and LEM IV are displayed

Fig. 3

Representative MR-images for the biological endpoint paresis grade II after carbon ion (¹²C–ion) and photon irradiation compared to an untreated control. The symptomatic animals show an edema (white arrowheads) and canalis centralis dilatation (red arrowhead) in the T2-weighted images as well as contrast agent (CA) accumulation in the T1-weighted images (lowest row, white asterisks)

Fig. 4

Histological sections representative for the biological endpoint paresis grade II. Cryosections stained with hemalum/eosin in combination with Luxol fast blue (a-c). A clear structural decline in the white matter represented by necrosis (asterisk) and vacuolization (open arrows) as well as hemorrhages (white arrows) and dilated blood vessels (closed black arrows) can be seen (b, c). Paraffin sections for detection of albumin extravasation (brown precipitation) combined with Nissl staining (d-f). Albumin leaks predominately in the area where structural decline of white matter occurs (black asterisks) and around the canalis centralis (white arrow heads). The leakage is more intense after carbon ion (e) than photon irradiation (f) (scale bar 200 μm)