Abstract
It is necessary to elucidate the individual effects of temozolomide (TMZ) on carcinogenesis and tumor resistance to chemotherapy mechanisms. The study aimed to investigate the TMZ 50 and 100 μM dose effect difference between PBT24 and SF8628 cell line high-grade pediatric glioblastoma (phGBM) xenografts in a chicken chorioallantoic membrane (CAM) model, on PCNA and EZH2 immunohistochemical expression in the tumor and on the expression of NKCC1, KCC2, E- and N-cadherin genes in TMZ-treated and control cell groups in vitro. TMZ at a 100 μg dose reduced the incidence of PBT24 xenograft invasion into the CAM, CAM thickening and the number of blood vessels in the CAM (p < 0.05), but did not affect the SF8628 tumor in the CAM model. The TMZ impact on PBT24 and SF8628 tumor PCNA expression was similarly significantly effective but did not alter EZH2 expression in the studied tumors. The TMZ at 50 μM caused significantly increased RNA expression of the NKCC1 gene in both studied cell types compared with controls (p < 0.05). The expression of the KCC2 gene was increased in PBT24 TMZ-treated cells (p < 0.05), and no TMZ effect was found in SF8628-treated cells. The study supports the suggestion that individual sensitivity to TMZ should be assessed when starting treatment.
Highlights
Pediatric high-grade glioblastoma multiforme is a highly malignant brain tumor and the most common cause of death [1]
Notwithstanding, patients having an initial response to TMZ fail therapy: approximately 55% of glioblastoma patients develop resistance to TMZ chemotherapy [5,6]. Pediatric high-grade glioblastoma multiforme (phGBM) is different from adult gliomas
The unique developmental origins and distinct biological factors of this heterogeneous group of tumors have highlighted the importance of avoiding treatment strategies based solely on adult glioblastoma, as this approach has not improved the outcome of phGBM [7]
Summary
Pediatric high-grade glioblastoma multiforme (phGBM) is a highly malignant brain tumor and the most common cause of death [1]. The standard glioblastoma treatment includes surgical resection, radiotherapy and temozolomide (TMZ) chemotherapy [3]. Following therapy with TMZ in adults, the treatment has employed TMZ for phGBM patients [2,4]. Notwithstanding, patients having an initial response to TMZ fail therapy: approximately 55% of glioblastoma patients develop resistance to TMZ chemotherapy [5,6]. The unique developmental origins and distinct biological factors of this heterogeneous group of tumors have highlighted the importance of avoiding treatment strategies based solely on adult glioblastoma, as this approach has not improved the outcome of phGBM [7]. Individual TMZ effectiveness depends on the resistance to TMZ, which would cause glioblastoma recurrence and a worse outcome [8]. It is essential to determine individual sensitivity to TMZ treatment and the personal effect of TMZ on cancerogenesis, which is critical for effective treatment
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