Memory and survival after microbeam radiation therapy
Introduction
Better therapies are needed to palliate malignant brain tumours, particularly in children. Conventional irradiation of the brain with high cumulative doses has been shown to increase survival time significantly in many cases, but may result in considerable delayed tissue damage and severe cognitive dysfunction.
MRT can be described as a special form of radiotherapy. A multislit collimator is used that allows the generation of a planar array of microbeams in the setting of a synchrotron facility. As a result, X-ray doses up to two magnitudes higher than those ordinarily used in the hospital can be deposited in the tumour location in one single fraction. Previous studies have shown that the overall structure of the normal tissue between the paths of the microbeams stays intact and function is preserved [1], [2]. No white matter necrosis was seen even when single-fraction doses as high as 500 Gy were administered [3].
Radioresistant tumours have been found to contain high levels of the cytoprotective tripeptide glutathione [4], [5]. Thus, a compound that lowers glutathione levels in the tumour should reduce its radioresistance. Miura and Sasaki [6] have shown in vitro that addition of buthionine-SR-sulfoximine (BSO) to the growth medium decreased the cellular glutathione levels and increased the radiosensitivity of the cells. A number of studies have shown that administration of glutamine promotes glutathione synthesis in normal tissue but paradoxically depletes glutathione levels in tumour tissue. Dietary glutamine has been shown to decrease glutathione levels in animal models of breast tumour [7] and fibrosarcoma [8].
Section snippets
Materials and methods
Animal models. C6 glioma in adult male Wistar rats and F98 glioma in adult male Fischer rats were used as animal models for the malignant human brain tumour glioblastoma multiforme. A total of 51 Wistar rats (298–330 g) and 49 Fischer rats (274–294 g) were used for these experiments. Animals were housed and cared for in a temperature-regulated animal facility exposed to a 12-hour light/dark cycle and experiments performed in accordance with the guidelines of the French and Canadian Councils on
Results
In both animal models of malignant brain tumour, a statistically significant increase of survival time was observed with MRT as compared to untreated animals (p = 0.0354 for F98 glioma and p = 0.0005 for C6 glioma; Fig. 2, Fig. 3). In both models, a further survival increase was observed with administration of BSO at 2 h prior to MRT. The increase in survival time between treatment groups undergoing MRT only and MRT after injection of BSO was statistically significant for F98 gliomas (p = 0.0014) but
Discussion
From the results of our study it is clear that our MRT protocol significantly increases survival time in both animal models of malignant brain tumour. The 1-year survival rate of animals with C6 glioma after MRT alone was already 50% and increased to 66.7% by administration of BSO. In animals with F98, only 3 out of 12 (25%) animals that underwent MRT alone survived 1 month. The 1-month survival rate was increased to 66.7% with administration of BSO prior to MRT. These observations support the
Conclusions
We were able to show that it is possible, in two animal models of malignant brain tumour, to increase survival with a bi-directional MRT protocol, and further with adjuvant therapy (BSO). BSO administration was followed by significant memory dysfunction early after treatment. This memory dysfunction significantly improved over time in tumour-bearing animals, but not in tumour-free animals, which shows the importance of exact pre-treatment planning to restrict high-dose therapy and BSO
Conflict of interest
All authors declare that they have no conflicts of interest.
Acknowledgments
We would like to thank Prof. Esther Shohami from The Hebrew University, Jerusalem, for introducing us to the ORT. Further we would like to thank Mr. Dominique Dallery and Dr. Geraldine LeDuc (ESRF) for their help preparing the animal experiments, Ms. Connie Wong (University of Saskatchewan) and Ms. Catherine Massart (INSERM) for help in the cell culture laboratory and Ms. Mehri Herman for help with the animal care at the University of Saskatchewan. The MRT experiments were performed at the
References (13)
- et al.
A new one-trial test for neurobiological studies of memory in rats. 1. Behavioral data
Behav Brain Res
(1988) - et al.
Detailed analysis of the behavior of Lister and Wistar rats in anxiety, object recognition and object location tasks
Behav Brain Res
(2005) - et al.
Weanling piglet cerebellum: a surrogate for tolerance to MRT (microbeam radiation therapy) in pediatric neuro-oncology
Proc SPIE
(2001) - et al.
Neuropathology of ablation of rat gliosarcomas and contiguous brain tissues using a microplanar beam of synchrotron-wiggler-generated X-rays
Int J Canc
(1998) - et al.
Response of rat intracranial 9L gliosarcoma to microbeam radiation therapy
Neuro-Oncology
(2002) - et al.
Effect of l-buthionine sulfoximine on the radiation response of human renal carcinoma cell lines
Cancer
(1993)