Synchrotron microbeam radiation therapy for rat brain tumor palliation - Influence of the microbeam width at constant valley dose

Université de Toulouse, UPS, Centre de Recherche Cerveau et Cognition, France.
Physics in Medicine and Biology (Impact Factor: 2.76). 11/2009; 54(21):6711-24. DOI: 10.1088/0031-9155/54/21/017
Source: PubMed


To analyze the effects of the microbeam width (25, 50 and 75 microm) on the survival of 9L gliosarcoma tumor-bearing rats and on toxicity in normal tissues in normal rats after microbeam radiation therapy (MRT), 9L gliosarcomas implanted in rat brains, as well as in normal rat brains, were irradiated in the MRT mode. Three configurations (MRT25, MRT50, MRT75), each using two orthogonally intersecting arrays of either 25, 50 or 75 microm wide microbeams, all spaced 211 microm on center, were tested. For each configuration, peak entrance doses of 860, 480 and 320 Gy, respectively, were calculated to produce an identical valley dose of 18 Gy per individual array at the center of the tumor. Two, 7 and 14 days after radiation treatment, 42 rats were killed to evaluate histopathologically the extent of tumor necrosis, and the presence of proliferating tumors cells and tumor vessels. The median survival times of the normal rats were 4.5, 68 and 48 days for MRT25, 50 and 75, respectively. The combination of the highest entrance doses (860 Gy per array) with 25 microm wide beams (MRT25) resulted in a cumulative valley dose of 36 Gy and was excessively toxic, as it led to early death of all normal rats and of approximately 50% of tumor-bearing rats. The short survival times, particularly of rats in the MRT25 group, restricted adequate observance of the therapeutic effect of the method on tumor-bearing rats. However, microbeams of 50 microm width led to the best median survival time after 9L gliosarcoma MRT treatment and appeared as the better compromise between tumor control and normal brain toxicity compared with 75 microm or 25 microm widths when used with a 211 microm on-center distance. Despite very high radiation doses, the tumors were not sterilized; viable proliferating tumor cells remained present at the tumor margin. This study shows that microbeam width and peak entrance doses strongly influence tumor responses and normal brain toxicity, even if valley doses are kept constant in all groups. The use of 50 microm wide microbeams combined with moderate peak doses resulted in a higher therapeutic ratio.

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    • "Moreover, using a microbeam SR with a very small beam spot permits the precise irradiation of single cells on a scale of micrometers. This feature can be regarded as an advantage, especially in radiotherapy , where the irradiated healthy tissue in the paths of the microbeam appears to be reduced [24]. Also, SR based medical imaging can produce images with high resolutions and a smaller dose is delivered to the tissue [25]. "
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    ABSTRACT: In this study, the total yields of SSB and DSB induced by monoenergetic electrons with energies of 0.28–4.55 keV, corresponding to ultrasoft X-rays energies, have been calculated in Charlton and Humm volume model using the Geant4-DNA toolkit and compared with theoretical and experimental data. A reasonable agreement between the obtained results in the present study and experimental and theoretical data of previous studies showed the efficiency of this model in estimating the total yield of strand breaks in spite of its simplicity. Also, it has been found that in the low energy region, the yield of the total SSB remains nearly constant while the DSB yield increases with decreasing energy. Moreover, a direct dependency between DSB induction, RBE value and the mean lineal energy as a microdosimetry quantity has been observed. In addition, it has become clear that the use of the threshold energy of 10.79 eV to calculate the total strand breaks yields results in a better agreement with the experiments, while the threshold of 17.5 eV shows a big difference.
    Nuclear Instruments and Methods in Physics Research Section B Beam Interactions with Materials and Atoms 01/2015; 342. DOI:10.1016/j.nimb.2014.10.023 · 1.12 Impact Factor
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    • "Slatkin et al. [5] proposed an MRT to treat brain tumors and confirmed that normal tissue has extremely high tolerance to microplanar beam X-rays [6]. Laissue et al. [7] demonstrated that MRT is effective in increasing the life span of rats bearing brain tumors, and since then, many results for synchrotron radiation have been accumulated with regards to its sparing effects on normal tissue [8] [9] [10] [11] [12] and therapeutic effects in tumor bearing animals [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23]. MRT is a spatially fractionated radiation therapy with parallel beams of mainly 25–50 µm beam width and 100–500 µm center-to-center separation, at a peak dose of 100–600 (usually 300) Gy from one direction or orthogonally arranged multiple directions of a single shot from each direction. "
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    ABSTRACT: A Monte Carlo simulation was applied to study the energy dependence on the transverse dose distribution of microplanar beam radiation therapy (MRT) for deep-seated tumors. The distribution was found to be the peak (in-beam) dose and the decay from the edge of the beam down to the valley. The area below the same valley dose level (valley region) was decreased with the increase in the energy of X-rays at the same beam separation. To optimize the MRT, we made the following two assumptions: the therapeutic gain may be attributed to the efficient recovery of normal tissue caused by the beam separation; and a key factor for the efficient recovery of normal tissue depends on the area size of the valley region. Based on these assumptions and the results of the simulated dose distribution, we concluded that the optimum X-ray energy was in the range of 100-300 keV depending on the effective peak dose to the target tumors and/or tolerable surface dose. In addition, we proposed parameters to be studied for the optimization of MRT to deep-seated tumors.
    Journal of X-Ray Science and Technology 05/2014; 22(3):395-406. DOI:10.3233/XST-140434 · 1.40 Impact Factor
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    • "Th erefore, our study used not only a widely used dosage (4 Gy), but also a very high dosage (40 Gy) to test if the cell death mode may be signifi cantly changed when dosage reaches a very high level. (2) One of the major potential medical applications of SR X-ray is microbeam radiation therapy (MRT), which uses dosages at even higher than 40 Gy (Serduc et al. 2009). Because PARP activation plays signifi cant roles in cancer development and cancer treatment (Weaver and Yang 2013), in our study we determined the biological eff ects of 40 Gy SR X-ray on normal biological tissues, so as to establish a critical basis for future studies that compare the biological responses of normal tissues and tumor tissues in response to therapeutic doses of SR X-ray. "
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    ABSTRACT: Purposes: Synchrotron radiation (SR) X-ray has great potential for cancer treatment and medical imaging. It is of significance to investigate the mechanisms underlying the effects of SR X-ray irradiation on biological tissues, and search for the strategies for preventing the damaging effects of SR X-ray irradiation on normal tissues. The major aim of our current study is to test our hypothesis that poly(ADP-ribose) polymerase (PARP) plays a significant role in SR X-ray-induced tissue damage. Methods and materials: The testes of rodents were pre-treated with PARP inhibitor 3-aminobenzamide (3-AB) or antioxidant N-acetyl-acetylcysteine (NAC), followed by SR X-ray irradiation. PARP activation, double-strand DNA breaks (DSB), Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) signals, caspase-3 activity and weight of the testes were determined. Results: SR X-ray irradiation produced dose-dependent increases in poly(ADP-ribose) (PAR) formation - an index of PARP activation, which can be prevented by NAC administration. Administration of 10 or 20 mg/kg 3-AB attenuated a variety of tissue injury induced by SR X-ray, including caspase-3 activation, increases in TUNEL signals and loss of testical weight. The PARP inhibitor also significantly decreased SR X-ray-induced γ-H2AX signal - a marker of DSB. Conclusions: Our study has provided the first evidence suggesting that SR X-ray can induce PARP activation by generating oxidative stress, which leads to various tissue injuries at least partially by exacerbating DNA damage and apoptotic changes.
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