Survival of rats bearing advanced intracerebral F 98 tumors after glutathione depletion and microbeam radiation therapy: conclusions from a pilot project

Abstract

BackgroundResistance to radiotherapy is frequently encountered in patients with glioblastoma multiforme. It is caused at least partially by the high glutathione content in the tumour tissue. Therefore, the administration of the glutathione synthesis inhibitor Buthionine-SR-Sulfoximine (BSO) should increase survival time.MethodsBSO was tested in combination with an experimental synchrotron-based treatment, microbeam radiation therapy (MRT), characterized by spatially and periodically alternating microscopic dose distribution. One hundred thousand F98 glioma cells were injected into the right cerebral hemisphere of adult male Fischer rats to generate an orthotopic small animal model of a highly malignant brain tumour in a very advanced stage. Therapy was scheduled for day 13 after tumour cell implantation. At this time, 12.5% of the animals had already died from their disease.The surviving 24 tumour-bearing animals were randomly distributed in three experimental groups: subjected to MRT alone (Group A), to MRT plus BSO (Group B) and tumour-bearing untreated controls (Group C). Thus, half of the irradiated animals received an injection of 100 μM BSO into the tumour two hours before radiotherapy.Additional tumour-free animals, mirroring the treatment of the tumour-bearing animals, were included in the experiment. MRT was administered in bi-directional mode with arrays of quasi-parallel beams crossing at the tumour location. The width of the microbeams was ≈28 μm with a center-to-center distance of ≈400 μm, a peak dose of 350 Gy, and a valley dose of 9 Gy in the normal tissue and 18 Gy at the tumour location; thus, the peak to valley dose ratio (PVDR) was 31.ResultsAfter tumour-cell implantation, otherwise untreated rats had a mean survival time of 15 days. Twenty days after implantation, 62.5% of the animals receiving MRT alone (group A) and 75% of the rats given MRT + BSO (group B) were still alive. Thirty days after implantation, survival was 12.5% in Group A and 62.5% in Group B. There were no survivors on or beyond day 35 in Group A, but 25% were still alive in Group B. Thus, rats which underwent MRT with adjuvant BSO injection experienced the largest survival gain.ConclusionsIn this pilot project using an orthotopic small animal model of advanced malignant brain tumour, the injection of the glutathione inhibitor BSO with MRT significantly increased mean survival time.

Perampanel Add-on to Standard Radiochemotherapy in vivo Promotes Neuroprotection in a Rodent F98 Glioma Model

“…To conduct the in vivo experiments with respect to orthotopic glioma progression and onset of tumor-related seizures, a robust animal model was needed. F98 glioma in Fischer rats is a wellestablished glioma model (Belloli et al, 2013;Schültke et al, 2018;Wang et al, 2018), but to the best of our knowledge, no data about its tumor-associated epileptiform phenotype have been published so far (Kirschstein and Köhling, 2016). The results of our studies suggest that F98 glioma led to interictal epileptiform events (e.g., spikes and spike-waves), indicating a high susceptibility to develop seizures, which was also demonstrated by video-EEG analysis.…”

Animal Models in Microbeam Radiation Therapy: A Scoping Review

“…F98 glioma cells and C6 cells, implanted respectively in Wistar and Fisher rats, were used to demonstrate that two orthogonal, cross-planar MRT arrays (24.75 µm; 211 ctc; 350 Gy peak-dose) significantly increased survival as compared to untreated controls [40]. This effect was amplified when MRT was preceded by the administration of the glutathione synthesis inhibitor buthionine-SR-sulfoximine [41]. When two orthogonal MRTs (50 µm; 200 ctc; 241 Gy peak-dose and 10.5 Gy valley-dose) were compared to two orthogonal BB fields (10.5 Gy), MRT was more effective than BB in slowing F98 glioma growth and increasing tumour vessel permeability [42].…”

“…Given that PVDRs are likely to be lower for human treatments [91], a strategy which relies on relatively low peak-dose (100-250 Gy) by leveraging the immunomodulatory [29,53] or angio-disruptive effects of MRT [42,70] could strike an optimal balance between toxicity and tumour control. Previous studies have shown MRT to be effective for treating rat models of glioma when combined with chemotherapeutic agents [36,37,41] or immunotherapy [39]. Future studies should investigate the optimal dose, sequencing and timing of MRT in relation to chemotherapy and immunotherapy and whether there is a role for temporally fractionating the delivery of MRT.…”

Technical feasibility of [18F]FET and [18F]FAZA PET guided radiotherapy in a F98 glioblastoma rat model

“…A more accurate delineation of the BTV might be possible by using a small animal PET scanner with better spatial resolution. Secondly, taking into account the humane endpoints, several animals had to be euthanized early due to clinical deterioration as result of large tumors as previously described by Schültke et al [44]. This issue will influence the average values significantly.…”