Halogenated Pyrimidines as Radiosensitizers in the Treatment of Glioblastoma Multiforme
Douglas JacksonTimothy J. KinsellaJan RowlandDonald WrightDavid A. KatzDavid MainJerry M. CollinsPaul L. KornblithEli Glatstein
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Sixty patients with high-grade gliomas (including 50 patients with glioblastoma multiforme) were entered on four sequential Phase I trials combining continuous intravenous infusions of halogenated pyrimidines and high-dose brain irradiation. Patients received two 14-day infusions of bromodeoxyuridine (BUdR) or iododeoxyuridine (IUdR) during the initial wide field and later reduced field radiation treatment (total radiation dose 65–70 Gy). All patients were followed a minimum of 6 months or until death. The actuarial median survival was 13 months for the entire group, with an 18-month survival of 24%. No significant survival differences were observed based on BUdR versus IUdR, 12-h versus 24-h infusion schedule, degree of surgical resection, or sex. Good performance status and age under 50 years were significant favorable prognostic factors. Of interest, the 48 patients who completed planned treatment had a 14-month median survival, with a 30% 18-month survival. These survival observations are at least comparable to other combined modality trials in patients with glioblastoma multiforme. Ongoing and planned clinical trials using the halogenated pyrimidine analogs as radiosensitizers in patients with glioblastoma multiforme are discussed.Tumor progression
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Malignant glioma is the most common and aggressive primary brain tumor and the overall prognosis for glioma patients remains poor. Clarification of the molecular mechanism responsible for glioma progression is critical for the effective treatment of glioma. Melanoma antigen gene (MAGE)-A2 (MAGEA2) is a member of the MAGE-A family proteins widely studied for cancer vaccine development and identification of tumor markers. However, MAGEA2 clinical significance and biological function in glioma remain unclear, especially for the prognosis of glioma patients. This study investigates MAGEA2 expression in glioma tissue samples and its significance in predicting glioma patient prognosis. MAGEA2 protein expression in tissue samples was measured by immunohistochemistry and western blotting, and MAGEA2 mRNA expression was determined by real-time polymerase chain reaction. Our results confirmed that MAGEA2 mRNA and protein expression levels were upregulated in glioma tissues, compared with normal brain tissue. The high expression of MAGEA2 in glioma tissues significantly correlated with World Health Organization advanced grade. Univariate and multivariate analyses revealed that high MAGEA2 expression is an independent prognostic factor for glioma patient poor overall survival. The P53 mRNA expression levels were downregulated in glioma tissues compared to noncancerous brain tissue and MAGEA2 expression negatively correlated with P53 expression. Taken together, our results suggest that MAGEA2 plays an oncogenic role in glioma progression, and they provide insight into MAGEA2 application as a novel predictor of clinical outcomes and a potential glioma biomarker.
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Abstract Background: Glioma is a type of malignant cancer in the central nervous system. New predictive biomarkers have been investigated in recent years, but the clinical prognosis in glioma remains poor. The function of CPLX2 in glioma and the probable molecular mechanism of tumor suppression was the focus of this investigation. Methods: The glioma transcriptome profile is downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases were performed to analyze the expression of CPLX2 in glioma. RT-qPCR was performed to detect the expression of CPLX2 in 68 glioma subjects, these patients who have been followed up. Kaplan-Meier survival analyses were done to evaluate the effect of CPLX2 on the prognosis of glioma patients. The CPLX2 knockdown and overexpressed cell lines were constructed to investigate the effect of CPLX2 on glioma. The cell growth, colony formation, and tumor formation in xenograft were performed. Results: The expression of CPLX2 was downregulated in glioma and negatively correlated to the grade of glioma. The higher expression of CPLX2 predicted a longer survival through the analysis of Kaplan-Meier survival curves. Overexpressed CPLX2 impaired tumorigenesis in glioma progression both in vivo and in vitro . Knocking down of CPLX2 promoted the proliferation of the glioma cells. The analysis of GSEA and co-expression analysis revealed that CPLX2 may affect the malignancy of glioma by regulating hypoxia and inflammation pathway. Conclusions: Our data indicated that CPLX2 functioned as a tumor suppressor and could be used as a potential prognostic marker in glioma.
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Objective To discusse the expression of MMP-2 and MMP-9 in human glioma and glioma's invasiveness and to elucidate invasive mechanism.Methods The protein expression of MMP-2 and MMP-9 was detected through immunohistochemistry,and MMP-2 mRNA and MMP-9 mRNA were detected through in situ hybridization in glioma and glioma's invasive tissue.Results The positive expression of MMP-2 mRNA and MMP-9 mRNA in glioma was 5.26±1.47,9.51±0.96,14.58±1.42,20.56±1.56 and 7.90±0.50,14.46±0.75,23.54±1.32,28.07±0.81,respectively.The expression of MMP-2 mRNA and MMP-9 mRNA inⅠ~Ⅱgrade and Ⅲ~Ⅳgrade was 5.70±0.95,8.20±0.43 and 2.30±0.14,10.32±0.65,respecttively.Conclusions There is positive correlation with the malignant degree of glioma and the expression of MMP-2 and MMP-9.The glioma with high malignancy,comparing with low malignancy,shows stronger invasiveness.The more the expressions of MMP-2 and MMP-9 in glioma is,the stronger the invasive capacity is.The glioma's invasive tissue is the recurring source of glioma in clinical treatment,even after resecting glioma.
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Glioma is a tumor of the brain. Although the clinical regimens and surgical techniques for glioma have improved, therapies of advanced glioma remain challenging, carrying dismal overall survival and therapeutic success rates. Evidence has shown that miRNAs played important roles in glioma development. The current study aimed at investigating the function of a novel cancerogenic miRNA, miR-93, in glioma progression by investigating the expression and mechanism of it.qRT-PCR was conducted to assess the miR-93 expression and the mRNA expression of target gene in glioma tissues and cells. The invasion and migration abilities of the glioma cells were determined by transwell assays. Luciferase reporter assay was performed to confirm the target of miR-93.The results indicated that miR-93 expression in glioma tissues and cells was increased significantly than that in normal brain tissues and cells. Furthermore, miR-93 promoted glioma cell migration and invasion. RBL2 was recognized as a direct target of miR-93 in glioma cells, and overexpression of RBL2 could reverse the stimulative effect of miR-93 in glioma cell.The above findings suggested that miR-93 together with RBL2 could be diagnostic targets and novel prognostic markers for glioma.
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Glioma is the most common primary intracranial tumor and is related to poor clinical outcomes. The developments of sensitive markers can be applied to reveal the mechanisms involved in the progression of glioma. This study examined CDCA2 expression in glioma samples and its significance in predicting glioma patient outcome. GEPIA and GEO datasets were used to explore the expression of CDCA2 in glioma. Kaplan-Meier and multivariate assays were applied to delve into the prognostic values of CDCA2 expression in glioma patients using CGGA datasets. Our group also determined the associations between CDCA2 and clinical characteristics. Coexpression analysis was performed. In this research, we observed that CDCA2 expression was distinctly upregulated in glioma specimens compared with nontumor specimens. The prognosis of glioma with high CDCA2 expression was distinctly worse compared with that of glioma with low CDCA2 expression. Additionally, multivariate Cox regression analysis revealed that high CDCA2 expression was an independent poor prognostic indicator for glioma patients. High expression of CDCA2 was positively associated with advanced clinical progression. Coexpression analysis revealed that CDCA2 could be positively related to ASPM, SKA1, DLGAP5, NCAPG, and CDCA8 and was negatively associated with ETNPPL, LDHD, MRVI1, CBX7, and CENPJ. Overall, our findings revealed that CDCA2 might serve as an independent prognosis indicator for glioma.
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