Biology contributions
Regional differences in radiosensitivity across the rat cervical spinal cord

https://doi.org/10.1016/j.ijrobp.2004.10.018Get rights and content

Purpose

To study regional differences in radiosensitivity within the rat cervical spinal cord.

Methods and materials

Three types of inhomogeneous dose distributions were applied to compare the radiosensitivity of the lateral and central parts of the rat cervical spinal cord. The left lateral half of the spinal cord was irradiated with two grazing proton beams, each with a different penumbra (20–80% isodoses): lateral wide (penumbra = 1.1 mm) and lateral tight (penumbra = 0.8 mm). In the third experiment, the midline of the cord was irradiated with a narrow proton beam with a penumbra of 0.8 mm. The irradiated spinal cord length (C1–T2) was 20 mm in all experiments. The animals were irradiated with variable single doses of unmodulated protons (150 MeV) with the shoot-through method, whereby the plateau of the depth–dose profile is used rather than the Bragg peak. The endpoint for estimating isoeffective dose (ED50) values was paralysis of fore and/or hind limbs within 210 days after irradiation. Histology of the spinal cords was performed to assess the radiation-induced tissue damage.

Results

High-precision proton irradiation of the lateral or the central part of the spinal cord resulted in a shift of dose–response curves to higher dose values compared with the homogeneously irradiated cervical cord to the same 20-mm length. The ED50 values were 28.9 Gy and 33.4 Gy for the lateral wide and lateral tight irradiations, respectively, and as high as 71.9 Gy for the central beam experiment, compared with 20.4 Gy for the homogeneously irradiated 20-mm length of cervical cord. Histologic analysis of the spinal cords showed that the paralysis was due to white matter necrosis. The radiosensitivity was inhomogeneously distributed across the spinal cord, with a much more radioresistant central white matter (ED50 = 71.9 Gy) compared with lateral white matter (ED50 values = 28.9 Gy and 33.4 Gy). The gray matter did not show any noticeable lesions, such as necrosis or hemorrhage, up to 80 Gy. All lesions induced were restricted to white matter structures.

Conclusions

The observed large regional differences in radiosensitivity within the rat cervical spinal cord indicate that the lateral white matter is more radiosensitive than the central part of the white matter. The gray matter is highly resistant to radiation: no lesions observable by light microscopy were induced, even after a single dose as high as 80 Gy.

Introduction

In radiation oncology it is a major goal to irradiate the tumor with the highest possible dose with minimal morbidity of the normal tissue. Therefore, it is of great importance to know the adverse effects of inhomogeneous dose distributions on normal tissues and to be able to estimate normal tissue complication probabilities.

The total dose to the planning target volume is limited by the tolerance of surrounding healthy tissues. When a tumor is located near a critical organ, as often occurs with the spinal cord, the dose is likely to be inhomogeneously distributed across the cord. Although this situation is common in clinical practice, the influence of this inhomogeneous dose distribution on the tolerance of the spinal cord is not known. For homogeneously irradiated rat spinal cord with lengths <2 cm, it is known that the isoeffective dose (ED50) for white matter necrosis decreases with increasing irradiated volume (1, 2, 3). In a recently published study (4) addressing inhomogeneous dose distributions over the longitudinal axis of the cord, we observed an unexpectedly large decrease of the ED50 for white matter necrosis for a 4-mm cord length when single doses as low as 4 Gy (bath doses) were applied to the regions adjacent to the 4-mm region. Histology of the spinal cord from paralyzed rats showed white matter necrosis predominantly in the lateral parts of the cord, without morphologic changes in the gray matter.

The pathogenesis of radiation-induced white matter necrosis is still not clear. Classically, the development of white matter necrosis has been considered a manifestation of a reduced number of surviving clonogens of either vascular or parenchymal target populations (5). Morris et al. (6) showed in boron neutron capture therapy experiments that endothelial cells were the most likely critical target population. There are several observations that, after irradiation, the oligodendrocyte progenitor cell (OPC)–depleted areas were repopulated by OPCs from adjacent unirradiated regions (7, 8, 9).

In the present study, we investigated the dose–response relationships for different regions across the rat cervical spinal cord. We selectively irradiated the left lateral half and a longitudinal slice along the midline of the spinal cord with a high-precision proton beam (150 MeV unmodulated protons), with a wide range of doses in gray and white matter. The obtained dose–response relationships are compared with a homogeneously irradiated 20-mm length of cervical cord (1). These experiments have benefited from the dose–distribution advantages of protons over the use of X-rays (mega- or kilovoltage). For protons, the penumbra at a 3-cm depth is as steep as could be achieved with orthovoltage X-rays, but contrary to orthovoltage X-rays, the depth–dose profile is more or less constant. This allows a very precise knowledge of the dose distribution in an absolute sense. The results of the experiments indicate that the higher radiosensitivity of the white matter compared with gray matter is not solely attributable to blood vessel damage and that a large difference exists between the sensitivity of central compared with more lateral regions of the white matter.

Section snippets

Animals

Male Wistar rats weighing 200–250 g were used. After irradiation, the animals were housed 2 per cage and provided with food and water ad libitum. All experiments were carried out in agreement with The Netherlands Experiments on Animals Act (1977) and The European Convention for the Protection of Vertebrates Used for Experimental Purpose (Strasbourg, 18.III.1986).

Experimental setup

Six rats were anesthetized (2.5% isoflurane at 0.75 O2 L/min for 10 min) and were placed vertically at equal distances in a Perspex

Grazing beam experiment

The dose–response curves for the lateral wide and tight experiments shifted to higher doses compared with the dose–response curve for the 20-mm full field (Fig. 3). The lateral tight irradiation, with a 0.3-mm smaller penumbra, resulted in a 4.5-Gy higher ED50 than the lateral wide irradiation. Both the lateral wide and tight experiments showed significantly higher ED50 than the 20-mm full field (Table 1).

The 100% isodose in both experiments was located at the lateral part of the white matter.

Discussion

With a high-precision proton beam, this study showed that the white matter in the left lateral half of the mature rat cervical spinal cord was more sensitive to radiation than the white matter in the middle part. This is expressed in a large shift to higher doses of the dose–response curve for the central beam compared with the grazing beams (Fig. 3), with a significantly higher radiosensitivity (ED50 values of 71.9 Gy compared with 28.9 and 33.4 Gy for the grazing beam experiments; Table 1).

Conclusions

This study showed for the first time large differences in radiosensitivity within the rat cervical spinal cord. These observations show that the lateral white matter is more radiosensitive than the central part of the white matter, suggesting that white matter necrosis is not just due to vascular endothelial damage, assuming the capillaries in the white matter to be homogeneously distributed. The migration of progenitor cells is possibly involved in the restoration of radiation-induced white

Acknowledgments

The excellent technical assistance of Harrie Kiewiet, Hette Faber, Femmy Cotteleer, Martha Ritsema, Wenny Peeters, and Annet Verleg is gratefully acknowledged.

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    Dr. Schippers's present address is the Paul Scherrer Institut, Villigen, Switzerland.

    This study is a part of the Proton Therapy Project Groningen, financed (Centrale Beleiosruimte RUG [CBR]) by the University of Groningen in The Netherlands.

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