Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To date, surgery and irradiation remain the standard therapies for anaplastic astrocytoma (AA, WHO grade III) and glioblastoma multiforme (GBM, WHO grade IV). Due to infiltrative tumor growth a complete surgical resection is never achieved and more than 90% of the tumors will recur within 2 cm of the primary tumor location. Postoperative radiotherapy prolongs survival but is not curative and prognosis remains poor with only a few patients being alive 2 years after diagnosis. Over the past decades multiple trials dealt with the question of whether chemotherapy (CT) may influence the outcome of malignant brain tumor patients. In general, the results have been disappointing with one exception: chemosensitivity and prolonged survival after CT have been demonstrated for tumors of oligodendrogial lineage. Drugs showing some activity in malignant brain tumors and therapeutic concepts will be discussed.
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PMID:Chemotherapy for malignant brain tumors of astrocytic and oligodendroglial lineage. 1121 19

The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) plays a pivotal role in alkylating drug resistance. Here, we determined MGMT activity in primary and recurrent glioblastomas (GBM, WHO grade IV) of patients who received radiation therapy (RT) or RT plus chemotherapy with alkylating agents (temozolomide, chloroethylnitrosoureas). The mean MGMT activity of untreated GBM was 37 +/- 45 (range 0-205) fmol/mg proteins. In the 1st, 2nd and 3rd recurrences, MGMT activity increased from 66 +/- 50 (13-194) to 68 +/- 44 (14-143) and 182 +/- 163 (64-423) fmol/mg protein, respectively. Comparing patients who received RT only with RT plus chemotherapy, a significant increase of MGMT in 1st recurrences was only found after treatment with RT plus chemotherapy, indicating either selection of MGMT expressing cells or induction of the MGMT gene by alkylating agents. The p53 status was not significantly related to the MGMT expression level, although a trend for lower MGMT activity in p53 positively stained tumors was observed. Patients expressing MGMT activity of <or=30 fmol/mg protein in the pretreatment tumor had a significant better therapeutic response than patients expressing MGMT above this level, which was shown by Kaplan-Meyer curves and the recurrence free interval after primary tumor resection. In patients who received RT only, this correlation was not found. The data revealed a threshold of MGMT expression (30 fmol/mg protein) below which patients respond better to alkylating agents. Therefore, determination of MGMT activity in the primary tumor appears to be useful in predicting the outcome of GBM therapy.
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PMID:MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome. 1800 Aug 22

GBM, the most common and malignant primary tumor of the CNS, is characterized by exponential growth and diffuse invasiveness. Although the diverse causative genotypes that give rise to a inhomogeneous histological phenotype are well defined, effective therapy inducing tumor cell apoptosis has not been established so far. Following surgery, billions of invasive tumor cells remain to be targeted by systemic and local therapies. Targeting non-overlapping pathways, rather than a single agent approach, is more likely to be effective. The potential of local drug application has not been exploited yet. Systemically, novel drug combinations have to be developed that not only target key molecules at the signaling crossroads but also exploit energy demand and the epigenetic cancer program of GBM.
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PMID:Translating biology into clinic: the case of glioblastoma. 1921 66

In this study, we investigated the effect of danthron on the cell migration and invasion of human brain glioblastoma multiforme GBM 8401 cells in vitro. The changes of migration and invasion of GBM 8401 cells after treatment with danthron were detected by cell migration assay and cell invasion assay. The levels of mRNA gene expression associated with cell migration and invasion were detected by real-time PCR. Results indicated that human brain glioblastoma multiforme GBM 8401 cells treated with danthron in vitro migrated and invaded less than cells treated with phosphate-buffered saline (PBS) (control). Western blotting showed that danthron inhibited the protein levels of FAK, MMP-7, MMP-9 and uPA in GBM 8401 cells. Real-time PCR assay also showed that danthron inhibited the mRNA expression of matrix metalloproteinase-9 (MMP-9), FAK and ROCK-1 of GBM 8401 cells. These results showed that danthron inhibited invasion and migration of GBM 8401 cells by downregulating mRNA expression associated with these processes, resulting in reduced metastasis. Thus, danthron may be considered a therapeutic agent that can inhibit primary tumor growth and prevent metastasis.
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PMID:Danthron inhibits the migration and invasion of human brain glioblastoma multiforme cells through the inhibition of mRNA expression of focal adhesion kinase, Rho kinases-1 and metalloproteinase-9. 1978 17

Cancers are driven by a population of cells with the stem cell properties of self-renewal and unlimited growth. As a subpopulation within the tumor mass, these cells are believed to constitute a tumor cell reservoir. Pathways controlling the renewal of normal stem cells are deregulated in cancer. The polycomb group gene Bmi1, which is required for neural stem cell self-renewal and also controls anti-oxidant defense in neurons, is upregulated in several cancers, including medulloblastoma. We have found that Bmi1 is consistently and highly expressed in GBM. Downregulation of Bmi1 by shRNAs induced a differentiation phenotype and reduced expression of the stem cell markers Sox2 and Nestin. Interestingly, expression of glycogen synthase kinase 3 beta (GSK3beta), which was found to be consistently expressed in primary GBM, also declined. This suggests a functional link between Bmi1 and GSK3beta. Interference with GSK3beta activity by siRNA, the specific inhibitor SB216763, or lithium chloride (LiCl) induced tumor cell differentiation. In addition, tumor cell apoptosis was enhanced, the formation of neurospheres was impaired, and clonogenicity reduced in a dose-dependent manner. GBM cell lines consist mainly of CD133-negative (CD133-) cells. Interestingly, ex vivo cells from primary tumor biopsies allowed the identification of a CD133- subpopulation of cells that express stem cell markers and are depleted by inactivation of GSK3beta. Drugs that inhibit GSK3, including the psychiatric drug LiCl, may deplete the GBM stem cell reservoir independently of CD133 status.
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PMID:GSK3beta regulates differentiation and growth arrest in glioblastoma. 1982 89

Glioblastoma multiforme is the most common primary tumor of the central nervous system. The drug temozolomide (TMZ) prolongs lifespan in many glioblastoma patients. The sensitivity of glioblastoma cells to TMZ is interfered by many factors, such as the expression of O-6-methylguanine-DNA methyltransferase (MGMT) and activation of AKT signaling. We have recently identified the interaction between netrin-4 (NTN4) and integrin beta-4 (ITGB4), which promotes glioblastoma cell proliferation via activating AKT-mTOR signaling pathway. In the current work we have explored the effect of NTN4/ITGB4 interaction on TMZ induced glioblastoma cell senescence. We report here that the suppression of either ITGB4 or NTN4 in glioblastoma cell lines significantly enhances cellular senescence. The sensitivity of GBM cells to TMZ was primarily determined by the expression of MGMT. To omit the effect of MGMT, we concentrated on the cell lines devoid of expression of MGMT. NTN4 partially inhibited TMZ induced cell senescence and rescued AKT from dephosphorylation in U251MG cells, a cell line bearing decent levels of ITGB4. However, addition of exogenous NTN4 displayed no significant effect on TMZ induced senescence rescue or AKT activation in U87MG cells, which expressed ITGB4 at low levels. Furthermore, overexpression of ITGB4 combined with exogenous NTN4 significantly attenuated U87MG cell senescence induced by TMZ. These data suggest that NTN4 protects glioblastoma cells from TMZ induced senescence, probably via rescuing TMZ triggered ITGB4 dependent AKT dephosphorylation. This suggests that interfering the interaction between NTN4 and ITGB4 or concomitant use of the inhibitors of the AKT pathway may improve the therapeutic efficiency of TMZ.
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PMID:NETRIN-4 protects glioblastoma cells FROM temozolomide induced senescence. 2426 16

5-aminolevulinic acid (5-ALA) has been used for the last 5 years to increase the extent of resection in adult brain tumors, mostly glioblastomas, but it is not approved yet as standard adjuvant treatment in the pediatric population. We report three different cases of pediatric brain tumors (two glioblastomas and one medulloblastoma) recently operated using 5-ALA fluorescence guidance, highlighting how useful it is in pediatric high-grade glioma (but not in medulloblastoma) also and confirming the lack of 5-ALA-related side effects. The first glioma was a recurrent GBM, whilst the second was a primary tumor. In all children, 5-ALA was administrated after discussing its use, including pros and cons, with the parents. 5-ALA fluorescence was a very useful tool to better identify tumor tissue and achieve gross-total tumor resection in GBMs, as confirmed by postoperative magnetic resonance imaging (MRI). In the medulloblastoma case no useful 5-ALA fluorescence was identified. No hematological or dermatological complications nor other side effects related to use of 5-ALA were observed. We submit that 5-ALA fluorescence guided surgery can be safe and useful in pediatric high-grade glioma, although its use in children still remains an off-label indication and requires validation through larger studies.
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PMID:5-ALA fluorescence-assisted surgery in pediatric brain tumors: report of three cases and review of the literature. 2479 77

Malignant glioma is the most common primary tumor of the central nervous system. Chemotherapy and radiotherapy are the most common therapeutic approaches in glioma therapy. Both processes mainly kill cancer cells through generating high Reactive Oxygen Species (ROS) and lead to oxidative DNA damage. However, tumor resistance to ROS is always a challenge for cancer treatment. Human Mut T homolog 1 (MTH1, also known as NUDT1) is regarded as a protector of nucleotides against oxidization. Recent reports have verified that overexpression of MTH1 could remove oxidized dNTP pools. Here, we find that MTH1 is overexpressed both at mRNA and protein levels in GBM. MTH1 silencing inhibits colony formation; tumor spheres formation and xenograft tumor growth, and more importantly, the viability of glioma cells is significantly decreased in H2O2 after MTH1 was knocked down in glioma. PI staining show that H2O2 cause more glioma cell death after MTH1 silencing. So we speculate that overexpression of MTH1 is crucial for glioma survival, suppression of its expression can inhibit cancer cell survival in vitro and in vivo, MTH1 may be a potential target for human glioma therapy in future.
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PMID:Birth of MTH1 as a therapeutic target for glioblastoma: MTH1 is indispensable for gliomatumorigenesis. 2739 63

Glioblastoma is highly aggressive. Early dispersal of the primary tumor renders localized therapy ineffective. Recurrence always occurs and leads to patient death. Prior studies have shown that dispersal of Glioblastoma can be significantly reduced by Dexamethasone (Dex), a drug currently used to control brain tumor related edema. However, due to high doses and significant side effects, treatment is tapered and discontinued as soon as edema has resolved. Prior analyses of the dispersal inhibitory effects of Dex were performed on tissue culture plastic, or polystyrene filters seeded with normal human astrocytes, conditions which inherently differ from the parenchymal architecture of neuronal tissue. The aim of this study was to utilize an ex-vivo model to examine Dex-mediated inhibition of tumor cell migration from low-passage, human Glioblastoma neurospheres on multiple substrates including mouse retina, and slices of mouse, pig, and human brain. We also determined the lowest possible Dex dose that can inhibit dispersal. Analysis by Two-Factor ANOVA shows that for GBM-2 and GBM-3, Dex treatment significantly reduces dispersal on all tissue types. However, the magnitude of the effect appears to be tissue-type specific. Moreover, there does not appear to be a difference in Dex-mediated inhibition of dispersal between mouse retina, mouse brain and human brain. To estimate the lowest possible dose at which Dex can inhibit dispersal, LogEC50 values were compared by Extra Sum-of-Squares F-test. We show that it is possible to achieve 50% reduction in dispersal with Dex doses ranging from 3.8 x10-8M to 8.0x10-9M for GBM-2, and 4.3x10-8M to 1.8x10-9M for GBM-3, on mouse retina and brain slices, respectively. These doses are 3-30-fold lower than those used to control edema. This study extends our previous in vitro data and identifies the mouse retina as a potential substrate for in vivo studies of GBM dispersal.
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PMID:Dexamethasone-mediated inhibition of Glioblastoma neurosphere dispersal in an ex vivo organotypic neural assay. 2904 Mar 22

OBJECTIVE Tectal gliomas constitute a rare and inhomogeneous group of lesions with an uncertain clinical course. Because these supposedly benign tumors are frequently followed up by observation over many years, the authors undertook this analysis of their own case series in an effort to demonstrate that the clinical course is highly variable and that there is a potential for a progressive biology. METHODS Clinical data analysis of 23 cases of tectal glioma (involving 9 children and 14 adults) was performed retrospectively. Radiographic data were analyzed longitudinally and MR images were evaluated for tumor volume, contrast enhancement, and growth progression. Quality of life was assessed using the EORTC BN20 and C30 questionnaires during follow-up in a subgroup of patients. RESULTS The patients' mean age at diagnosis was 29.2 years. The main presenting symptom at diagnosis was hydrocephalus (80%). Six patients were treated by primary tumor resection (26.1%), 3 patients underwent biopsy followed by resection (13.1%), and 3 patients underwent biopsy only (13.1%). For additional treatment of hydrocephalus, 14 patients (60.9%) received shunts and/or endoscopic third ventriculostomy. Radiographic tumor progression was observed in 47.9% of the 23 cases. The mean time between diagnosis and growth progression was 51.5 months, and the mean time to contrast enhancement was 69.7 months. Histopathological analysis was obtained in 12 cases (52.2%), resulting in 5 cases of high-grade glioma (3 cases of glioblastoma multiforme [GBM], grade IV, and 2 of anaplastic astrocytoma, grade III), 5 cases of pilocytic astrocytoma, 1 diffuse astrocytoma, and 1 ganglioglioma. Malignant progression was observed in 2 cases, with 1 case progressing from a diffuse astrocytoma (grade II) to a GBM (grade IV) within a period of 13 years. Quality-of-life measurements demonstrated distinct functional deficits compared to a healthy sample as well as glioma control cohorts. CONCLUSIONS Analysis of this case series shows that a major subpopulation of tectal gliomas show progression and malignant transformation in children as well as in adolescents. These tumors therefore cannot be considered inert lesions and require histological confirmation and close follow-up. Quality-of-life questionnaires show that tectal glioma patients might benefit from special psychological support in emotional, social, and cognitive functionality.
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PMID:Tectal gliomas: assessment of malignant progression, clinical management, and quality of life in a supposedly benign neoplasm. 2985 60


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