Abstract
BackgroundValproate (VPA) is a commonly prescribed antiepileptic drug for patients experiencing epileptic seizures due to brain tumors. VPA increases radiation sensitivity in various tumor cells in vitro due to complex mechanisms. This could make tumors more vulnerable to ionizing radiation or overcome radioresistance. Yet, clinical data on possible improvement of tumor control by adding VPA to tumor therapy is controversial. Potentially radiosensitizing effects of VPA on healthy tissue remain unclear. To determine individual radiosensitivity, we analyzed blood samples of individuals taking VPA.MethodsEx vivo irradiated blood samples of 31 adult individuals with epilepsy were studied using 3-color fluorescence in situ hybridization. Aberrations in chromosomes 1, 2 and 4 were analyzed. Radiosensitivity was determined by the mean breaks per metaphase (B/M) and compared to age-matched (2:1) healthy donors.ResultsThe patient cohort (n = 31; female: 38.7%) showed an increase of their average B/M value compared to healthy individuals (n = 61; female: 56.9%; B/M: 0.480 ± 0.09 vs. 0.415 ± 0.07; p = .001). The portion of radiosensitive (B/M > 0.500) and distinctly radiosensitive individuals (B/M > 0.600) was increased in the VPA group (54.9% vs. 11.3 and 9.7% vs. 0.0%; p < .001). In 3/31 patients, radiosensitivity was determined prior to and after VPA treatment and radiosensitivity was increased by VPA-treatment.ConclusionsIn our study, we confirmed that patients treated with VPA had an increased radiosensitivity compared to the control group. This could be considered in patients taking VPA prior to the beginning of radiotherapy to avoid toxic side effects of VPA-treatment.
Highlights
Valproate (VPA) is a commonly prescribed antiepileptic drug for patients experiencing epileptic seizures due to brain tumors
VPA is an effective inhibitor of histone deacetylase (HDAC) which is involved in modulating chromatin structure and gene expression [1, 2]
VPA patients and healthy controls In total, blood of 93 individuals of different ages was studied for radiosensitivity by fluorescence in situ hybridization (FiSH)
Summary
Valproate (VPA) is a commonly prescribed antiepileptic drug for patients experiencing epileptic seizures due to brain tumors. While the radiosensitizing effects seem clearly evident in vitro and potential benefits for oncological treatment by rendering tumor cells more vulnerable to irradiation and overcoming radioresistance seem plausible [6, 14], evidence in clinical studies is sparse and controversial and tumor control was not improved by adding VPA to therapy regimes [15, 16]. It is well known that enhanced radiosensitivity is associated with an increase of both acute and late adverse effects of irradiation due Stritzelberger et al BMC Neurology (2020) 20:390 to various causes such as certain drugs like chloroquine or vemurafenib and diseases like Ataxia teleangiectasia or Nijmegen breakage syndrome in patients undergoing radiation treatment [17,18,19,20]. A dose reduction is recommended for distinctly radiosensitive patients [21, 22]
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