Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glioblastoma multiform is one of the most devastating primary tumors in neurooncology. We analyzed prognosis factors in patients with grade IV glioblastoma treated between 1993 and 1997. The 22 long-term survival patients (survival over 26 months) were extracted from our 30 years archives and the 2 populations are compared. The incidence was 2.6/100,000h/year, 62% male and 38% female, mean age 59 years, mean survival 12 months, median survival time 9 months. Multivariate analysis showed that younger age, surgical treatment and radiotherapy were all dependent prognosis factors for better survival. Statistically, survival was best for total surgical removal of tumors, followed by tumor gross resection then biopsy. Clinical status and inextirpable tumor location were also prognosis factors. The free interval time between total surgery and tumor reappearance was strongly correlated with survival (r=0.94). This suggests that some grade IV gliomas follow a quicker course, others exhibiting slow growth. Each of the prognosis factors was confirmed in the long-survival patients. Prevalence of all glioblastomes was 4.3%. Their mean age was 42 and mean survival 62 months. A larger proportion of these patients had total surgery and radiotherapy. The time lapse before tumor reappearance was longer. Deep tumor locations were less frequent. The proportion of secondary versus primary glioblastomas was the greatest difference between the long-term and regular survivors. Secondary glioblastomas were found in only 4% of the standard population and in 23 to 41% in the long-term survivors (p<0.01). Primary glioblastomas typically show EGFR over expression and mutation (variant III). The pathway to secondary glioblastoma involves early P53 mutation. Despite the fact that the anatomopathologist regards similar tissues under the microscope, these subtypes of glioblastomas are distinct disease entities which evolve through different genetic pathways and exhibit different outcomes.
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PMID:[Glioblastomas: clinical study and search for prognostic factors]. 1259 6

Malignant transformation of human gliomas is accompanied by extensive proliferation of stromal blood vessels. Recent data suggest mesenchymal transdifferentiation of neoplastic cells in various human cancers, including colon and breast cancer as well as gliosarcoma. In this study, we have analyzed proliferating stromal blood vessels in glioblastoma multiforme for the presence of mutations in the tumor suppressor gene TP53. Using tissue arrays derived from glioblastoma specimens, cases with significant immunohistochemical p53 accumulation were selected for molecular genetic detection of TP53 mutations in exons 5 to 8. None of the tumors included in this series displayed properties of gliosarcoma. Proliferating glomeruloid stromal vessels were isolated by laser microdissection from paraffin sections. In six cases, single-strand conformation polymorphism analysis for mutations of the TP53 gene in stromal blood vessels compared with adjacent tumor cells and subsequent DNA sequencing of the resulting DNA fragments were carried out. Glioblastoma cells of these cases exhibited TP53 mutations in exons 5, 7 and 8. None of these tumors showed TP53 mutations in microdissected samples from glomeruloid vessels. The absence of TP53 mutations in vascular stromal components of glioblastoma multiforme supports the hypothesis that microvascular proliferations originate from the tumor stroma and are not derived from transdifferentiated glioblastoma cells.
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PMID:Analysis of the TP53 gene in laser-microdissected glioblastoma vasculature. 1262 85

The transmembrane proto-oncogene receptor tyrosine kinase (RTK) ROS is an orphan receptor that is aberrantly expressed in neoplasms of the central nervous system. Here, we report the fusion of its carboxy-terminal kinase domain to the amino-terminal portion of a protein called FIG (Fused in Glioblastoma) in a human glioblastoma multiforme (GBM). By characterizing both FIG and ROS genes in normal and in U118MG GBM cells, we determined that an intra-chromosomal homozygous deletion of 240 kilobases on 6q21 is responsible for the formation of the FIG-ROS locus. The FIG-ROS transcript is encoded by 7 FIG exons and 9 ROS-derived exons. We also demonstrate that the FIG-ROS locus encodes for an in-frame fusion protein with a constitutively active kinase activity, suggesting that FIG-ROS may act as an oncogene. This is the first example of a fusion RTK protein that results from an intra-chromosomal deletion, and it represents the first fusion RTK protein isolated from a human astrocytoma.
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PMID:Fusion of FIG to the receptor tyrosine kinase ROS in a glioblastoma with an interstitial del(6)(q21q21). 1266 Oct 6

Glioblastoma (GB) is the most common subtype of primary brain tumor in adults. These tumors are highly invasive, very aggressive, and often infiltrate critical neurological areas within the brain. The mean survival time after diagnosis of GB has remained unchanged during the last few decades, in spite of advances in surgical techniques, radiotherapy, and also chemotherapy; patients' survival ranges from 9 to 12 months after initial diagnosis. In the same time frame, with our increasing understanding and knowledge of the physiopathology of several cancers, meaningful advances have been made in the treatment and control of several cancers, such as breast, prostate, and hematopoietic malignancies. Although a number of the genetic lesions present in GB have been elucidated and our understanding of the progressions of this cancer has increased dramatically over the last few years, it has not yet been possible to harness this information towards developing effective cures. In this review, we will focus on the classical ways in which GB is currently being treated, and will introduce a novel therapeutic modality, i.e., gene therapy, which we believe will be used in combination with classical treatment strategies to prolong the life-span of patients and to ultimately be able to control and/or cure these brain tumors. We will discuss the use of several vector systems that are needed to introduce the therapeutic genes within either the tumor mass, if these are not resectable, or the tumor bed, after successful tumor resection. We also discuss different therapeutic modalities that could be exploited using gene therapy, i.e., conditional cytotoxic approach, direct cytotoxicity, immunotherapy, inhibition of angiogenesis, and the use of pro-apoptotic genes. The advantages and disadvantages of each of the current vector systems available to transfer genes into the CNS are also discussed. With the advances in molecular techniques, both towards the elucidation of the physiopathology of GB and the development of novel, more efficient and less toxic vectors to deliver putative therapeutic genes into the CNS, it should be possible to develop new rationale and effective therapeutic approaches to treat this devastating cancer.
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PMID:Current and future strategies for the treatment of malignant brain tumors. 1266 89

Diosquinone [1], a naphthoquinone epoxide previously isolated from the root bark of Diospyros mespiliformis (Hostch) and D. tricolor [Ebenaceae] is been assessed for cytotoxicity activity against ten cancer cell lines by standard NIH method. The ethno-pharmacological claim of this plant and the previously observed good antibacterial activity of this compound among the others isolated from this plant suggest its probable cytotoxicity activity. Diosquinone was observed to be very active against most of the cancer cell lines. It shows very good activity against all the cell lines tested with ED50 value ranging between 0.18 microg/ml. against Human Glioblastoma (U373) to 4.5 microg/ml. against Hormone dependent human prostrate cancer( LNCaP).
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PMID:In vitro cytotoxicity activity of Diosquinone, a naphthoquinone epoxide. 1267 63

Glioblastoma (GBM) remains one of the most challenging solid cancers to treat due to its highly proliferative, angiogenic and invasive nature. The small molecule CDK inhibitor, flavopiridol, has demonstrated antitumor activity in human xenograft models and is currently in clinical trials showing efficacy in patients with advanced disease. We have developed an experimental animal model using the murine glioma GL261 cells as a novel in vivo system to screen potential therapeutic agents for GBM. Results of in vitro testing demonstrate that flavopiridol has several relevant clinical characteristics such as its ability to: 1. inhibit cell growth; 2. inhibit cell migration; 3. decrease expression of cyclin D1, CDK4 and p21; 4. induce apoptosis in cells with high levels of p27 expression; and 5. decrease the expression of the anti-apoptotic protein Bcl-2. The mechanism by which flavopiridol induces apoptosis is mitochondrial-mediated. We demonstrate by electron microscopy and immunohistochemistry that drug treatment induces mitochondrial damage that was accompanied by the release of cytochrome c into the cytosol together with the translocation of apoptosis inducing factor (AIF) into the nucleus. This finding in murine glioma cells differs from the mechanism of flavopiridolinduced cell death reported by us for human glioma cells (Alonso et al., Mol Cancer Ther 2003; 2:139) where drug treatment induced a caspase- and cytochrome c-independent pathway in the absence of detectable damage to mitochondria. In apoptotic human glioma cells only translocation of AIF into the nucleus occurred. Thus, the same drug kills different types of glioma cells by different mitochondrial-dependent pathways.
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PMID:Flavopiridol induces mitochondrial-mediated apoptosis in murine glioma GL261 cells via release of cytochrome c and apoptosis inducing factor. 1273 34

Glioblastoma (GBM) is the most important primary brain tumor, both in terms of its incidence and its devastating impact on the unfortunate patients who have it. Although several well-defined hereditary syndromes predispose to malignant gliomas, most cases occur in the absence of a such a syndrome. The role of environmental factors, based on the known associations to date, also appears limited when compared with the total number of patients affected. It is clear that much remains to be discovered to better elucidate the causes of GBM, but the increasing recognition of molecular subtypes may help advance this field. This review highlights current insights into the molecular epidemiology of GBM.
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PMID:Molecular epidemiology of glioblastoma. 1278 75

Glioblastoma is a life-threatening tumor in the human brain despite the fact that radio-chemotherapy inducing DNA damage has been improved in the last decade. Various studies focusing on the enhancement of the susceptibility of glioblastoma cells to DNA damage have been reported, which are aimed at more efficient treatment for the tumor. In this study, we show that radioresistant T98G glioblastoma cells can develop sensitivity to DNA damage induced by irradiation and etoposide as a result of the introduction of a DNA repair-associated histone, H2AX. Interestingly, when H2AX-transformed T98G cells were irradiated, Brca1 and Nbs1 were readily recruited in DNA double-strand break (DSB) foci and showed the G2/M-phase arrest of the cell cycle. Moreover, up-regulation of Brca1 was observed in H2AX-T98G cells after exposure to irradiation. Together with the evidence that H2AX transfection does not affect growth activities of non-tumor cells under genotoxic stimuli, this suggests that H2AX gene transfer would provide a new modality for radio-chemotherapy for glioblastomas, probably through overcoming the instability of the genome, and that Brca1 and Nbs1 might be crucial in this methodology.
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PMID:Histone H2AX sensitizes glioma cells to genotoxic stimuli by recruiting DNA double-strand break repair proteins. 1285 79

Enhanced expression of both integrin alpha v beta 3 and platelet-derived growth factor receptor (PDGFr) has been described in glioblastoma tumors. We therefore explored the possibility that integrin alpha v beta 3 cooperates with PDGFr to promote cell migration in glioblastoma cells, and extended the study to identify the Src family members that are activated on PDGF stimulation. Glioblastoma cells utilize integrins alpha v beta 3 and alpha v beta 5 to mediate vitronectin attachment. We found that physiologic PDGF stimulation (83 pm, 10 min) of vitronectin-adherent cells promoted the specific recruitment of integrin alpha v beta 3-containing focal adhesions to the cell cortex and alpha v beta 3-mediated cell motility. Analysis of PDGFr immunoprecipitates indicated an association of the PDGFr beta with integrin alpha v beta 3, but not integrin alpha v beta 5. Cells plated onto collagen or laminin, which engage different integrins, exhibited significantly less migration on PDGF stimulation, indicating a cooperation of alpha v beta 3 and the PDGFr beta in glioblastoma cells that promotes migration. Further analysis of the cells plated onto vitronectin indicated that PDGF stimulation caused an increase in Src kinase activity, which was associated with integrin alpha v beta 3. In the vitronectin-adherent cells, Lyn was associated preferentially with alpha v beta 3 both in the presence and absence of PDGF stimulation. In contrast, Fyn was associated with both alpha v beta 3 and alpha v beta 5. Moreover, PDGF stimulation increased the activity of Lyn, but not Fyn, in vitronectin-adherent cells, and the activity of Fyn, but not Lyn, in laminin-adherent cells. Using cells attached to mAb anti-alpha v beta 3 or mAb anti-integrin alpha 6, we confirmed the activation of specific members of the Src kinase family with PDGF stimulation. Down-regulation of Lyn expression by siRNA significantly inhibited the cell migration mediated by integrin alpha v beta 3 in PDGF-stimulated cells, demonstrating the PDGFr beta cooperates with integrin alpha v beta 3 in promoting the motility of vitronectin-adherent glioblastoma cells through a Lyn kinase-mediated pathway. Notably, the data indicate that engagement of different integrins alters the identity of the Src family members that are activated on stimulation with PDGF.
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PMID:The pattern of enhancement of Src kinase activity on platelet-derived growth factor stimulation of glioblastoma cells is affected by the integrin engaged. 1288 26

Glioblastoma is a lethal neoplasm resistant to conventional radiotherapy and chemotherapy. Natural born killer (NBK), also known as Bcl-2-interacting killer (BIK), is a death-promoting Bcl-2 family protein sharing with Bcl-2 only the Bcl homology 3 (BH3) domain. We here report that an adenoviral vector encoding NBK (Ad-NBK) uniformly induces cell death in 12 human malignant glioma cell lines. Ad-NBK-induced cell death involves neither quantitative mitochondrial cytochrome c release nor caspase 8, 9, 7, or 3 processing and is unaffected by the viral caspase inhibitor, cytokine response modifier A (CRM-A), or selective caspase 8 or 9 inhibitors. In contrast, Ad-NBK-induced cell death is inhibited by the broad-range caspase inhibitor, zVAD-fmk, or by adenoviral gene transfer of the X-linked inhibitor of apoptosis protein (XIAP). Further, Ad-NBK-induced cell death is inhibited by Bcl-2 or Bcl-xL gene transfer. Interestingly, Bcl-2- and Bcl-xL-transfected glioma cells, which are partially protected from Ad-NBK-induced cell death, accumulate much higher levels of NBK than are ever observed in control-infected cells. This indicates that complex formation with Bcl-2 or Bcl-xL sequesters NBK in an inactive form and that free NBK, rather than an NBK-mediated depletion of free antiapoptotic Bcl-2 family proteins, is the proximate mediator of Ad-NBK-induced cell death. Conversely, proteasome inhibition-mediated accumulation of NBK strongly enhances Ad-NBK-induced cell death. Finally, Ad-NBK-infected LN-229 glioma cells are not tumorigenic in nude mice. Thus Ad-NBK triggers an XIAP- and zVAD-fmk-sensitive cell death pathway in glioma cells with potential therapeutic value, provided that NBK expression can be selectively targeted to cancer cells.
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PMID:Adenoviral natural born killer gene therapy for malignant glioma. 1295 95


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