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 multiforme is the most common and most aggressive type of high grade tumor with a poor prognosis upon discovery. Based on earlier promising results earned with AN-162, a doxorubicin molecule linked to somatostatin (SST) analogue RC-160, it was our aim to determine the effect of AN-162 on DBTRG-05 glioblastoma cell line, and to test its efficacy in experimental brain tumors. We detected the expression of mRNA for somatostatin receptor (SSTR) subtypes 2 and 3 in DBTRG-05 cells with RT-PCR. Using ligand competition assay, specific high affinity receptors for somatostatin were found. The MTT assay showed that both AN-162 and doxorubicin (DOX) significantly inhibited cell proliferation and that there was no significant difference between the effects in vitro. Nude mice were xenografted with DBTRG-05 glioblastoma tumors. AN-162 showed a significant inhibition of tumor growth compared with the control group and the groups treated with equimolar doses of doxorubicin, somatostatin analogue RC-160, or the unconjugated mixture of doxorubicin plus RC-160. The tumor doubling time in the group of animals treated with AN-162 was extended and was significantly different from doubling times in the control group and in the other treatment groups. Our study clearly demonstrates a potent inhibitory effect of AN-162 in experimental glioblastoma, thus suggesting the possibility of its utilization in patients suffering from malignant brain cancer.
 ...
PMID:The inhibitory effect of a novel cytotoxic somatostatin analogue AN-162 on experimental glioblastoma. 2066 26

Ribonucleic acid interference (RNAi) is a powerful molecular tool that has potential to revolutionize the treatment of cancer. One major challenge of applying this technology for clinical application is the lack of site-specific carriers that can effectively deliver short interfering RNA (siRNA) to cancer cells. Here we report the development and assessment of a cancer-cell specific magnetic nanovector construct for efficient siRNA delivery and non-invasive monitoring through magnetic resonance imaging (MRI). The base of the nanovector construct is comprised of a superparamagnetic iron oxide nanoparticle core coated with polyethylene glycol (PEG)-grafted chitosan, and polyethylenimine (PEI). The construct was then further functionalized with siRNA and a tumor-targeting peptide, chlorotoxin (CTX), to improve tumor specificity and potency. Flow cytometry, quantitative RT-PCR, and fluorescence microscopy analyses confirmed receptor-mediated cellular internalization of nanovectors and enhanced gene knockdown through targeted siRNA delivery. The ability of this nanovector construct to generate specific contrast enhancement of glioblastoma cells was demonstrated through MR imaging. These findings suggest that this CTX enabled nanoparticle carrier may be well suited for delivery of RNAi therapeutics to brain cancer cells.
 ...
PMID:Chlorotoxin bound magnetic nanovector tailored for cancer cell targeting, imaging, and siRNA delivery. 2067 83

Glioblastoma (GBM) is the most aggressive and destructive form of brain cancer. Animal models that can unravel the mechanisms underlying its progression are needed to develop rational and effective molecular therapeutic approaches. In this study, we report the development of mouse models for spontaneous gliomas representing distinct progressive stages of disease that are governed by defined genetic alterations. Neural stem/progenitor cell (NPC)-specific constitutive Ras activation in vivo plus p53 deficiency led to development of primarily anaplastic astrocytoma (grade III), whereas combined loss of p53 plus p16(Ink4a)/p19(Arf) led to development of GBM (grade IV) at 100% penetrance within 6 weeks. These glioma models showed enhanced stem cell properties (stemness) accompanied by malignant progression. Notably, we determined that, in our models and in human specimens, downregulation of the homeodomain transcription factor NKX2.2, which is essential for oligodendroglial differentiation, was correlated with increased tumor malignancy. NKX2.2 overexpression by GBM-derived glioma-initiating cells (GIC) induced oligodendroglial differentiation and suppressed self-renewal capacity. By contrast, Nkx2.2 downregulation in mouse NPCs accelerated GBM formation. Importantly, the inhibitory effects of NXK2.2 on GIC self-renewal were conserved in human cells. Thus, our mouse models offer pathobiologically significant advantages to investigate the nature of brain tumors, with improved opportunities to develop novel mechanism-based therapeutic approaches.
 ...
PMID:NKX2.2 suppresses self-renewal of glioma-initiating cells. 2116 5

The view that there are cancer-initiating stem cells has led to a concerted effort to understand the nature of these cells. As in many tissues, rare populations of cancer stem cells have been characterized in neural cancers, including glioblastoma, medulloblastoma and epyndymoma. The ability of stem cells to undergo both symmetric (self-renewal) and asymmetric (division to produce a more differentiated cell) cell division is what defines them as stem cells. Understanding the molecular genetic mechanisms governing the self-renewal and proliferation of these cells will be important in developing novel more effective strategies which will perhaps lead to better treatments for many cancers, including some of the most difficult to treat, such as the most common and aggressive brain cancer, glioblastoma. This review will focus on the molecular genetic mechanisms which have recently been identified as being important for neural stem cell self-renewal in brain cancer.
 ...
PMID:Self-renewal mechanisms in neural cancer stem cells. 2119 91

Glioblastoma multiforme (GBM), WHO grade IV astrocytoma, is the most dramatic primary brain cancer with a very poor prognosis due to inevitable disease recurrence. Less than 10% of GBM patients are still alive 5 years after diagnosis despite a multimodal treatment with surgical resection of the tumor, radiation therapy and chemotherapy. Cellular immunotherapy in gliomas, one of the promising new therapies, has shown convincing results in some patients with induction of antitumor immune responses and prolonged survival. In particular, several patients treated with dendritic cell vaccinations have demonstrated systemic antigen-specific cytotoxicity and intratumor infiltration of cytotoxic T cells. However, this is not always correlated with clinical improvement because GBM cells have multiple mechanisms that lead to suppression of the patient's antitumor immune responses. This article will focus on some aspects of the systemic immunosuppression observed in GBM patients as well as the multiple mechanisms of local immunoresistance developed by GBM.
 ...
PMID:Mechanisms of immunomodulation in human glioblastoma. 2152 70

A series of ellipticinium derivatives with selective cytotoxicity towards brain tumor cell lines has been identified through in vitro screening against disease-oriented panels of human tumor cell lines. Unfortunately 9-methoxy-2-methylellipticinium, the lead compound of this series, has shown only very limited evidence for in vivo activity when examined in a variety of human tumor xenograft models. This lack of activity has been postulated to be due to metabolism. To address this issue, a derivative was synthesized which was blocked at the theoretically vulnerable 9-position and yet could be shown to retain brain tumor selectivity in vitro. In vivo xenograft testing was performed to assess the therapeutic potential of this second generation compound. To maintain continuity with the in vitro screening data, in vivo experimental therapeutic models were devised employing one of the in vitro sensitive cell lines, the U-251 glioblastoma. Cells were cultivated in vitro and injected into female athymic nude mice for therapeutic studies. The 9-chloro-derivative of the lead compound produced growth delay of subcutaneously implanted tumor cells when. administered by seven-day continuous infusion. Based on this evidence for activity in a systemic chemotherapy mode, further studies were conducted using an orthotopic brain cancer model. In three separate experiments, intracranial implantation of 1x10(7) tumor cells resulted in 100% mortality of control mice with median survival ranging from 15-18.5 days. In all experiments, mice treated by subcutaneous infusion with 9-chloro-2-methylellipticinium acetate showed increases in survival. Statistically significant effects and individual long-term survivors were observed in two experiments; These results provide support for the further preclinical development of 9-chloro-2-methylellipticinium acetate as a candidate for clinical trials against human brain cancer.
 ...
PMID:Therapeutic activity of 9-chloro-2-methylellipticinium acetate in an orthotopic model of human brain cancer. 2159 95

Cellular energy metabolism is one of the main processes affected during the transition from normal to cancer cells, and it is a crucial determinant of cell proliferation or cell death. As a support for rapid proliferation, cancer cells choose to use glycolysis even in the presence of oxygen (Warburg effect) to fuel macromolecules for the synthesis of nucleotides, fatty acids, and amino acids for the accelerated mitosis, rather than fuel the tricarboxylic acid cycle and oxidative phosphorylation. Mitochondria biogenesis is also reprogrammed in cancer cells, and the destiny of those cells is determined by the balance between energy and macromolecule supplies, and the efficiency of buffering of the cumulative radical oxygen species. In glioblastoma, the most frequent and malignant adult brain tumor, a metabolic shift toward aerobic glycolysis is observed, with regulation by well known genes as integrants of oncogenic pathways such as phosphoinositide 3-kinase/protein kinase, MYC, and hypoxia regulated gene as hypoxia induced factor 1. The expression profile of a set of genes coding for glycolysis and the tricarboxylic acid cycle in glioblastoma cases confirms this metabolic switch. An understanding of how the main metabolic pathways are modified by cancer cells and the interactions between oncogenes and tumor suppressor genes with these pathways may enlighten new strategies in cancer therapy. In the present review, the main metabolic pathways are compared in normal and cancer cells, and key regulations by the main oncogenes and tumor suppressor genes are discussed. Potential therapeutic targets of the cancer energetic metabolism are enumerated, highlighting the astrocytomas, the most common brain cancer.
 ...
PMID:Metabolism and brain cancer. 2177 21

Several case-control studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce risk for glioblastoma, an aggressive form of brain cancer. Prospective investigations have not observed such an association, but these studies lacked adequate brain cancer case numbers and did not stratify by histologic subtype. We prospectively investigated the association between NSAID use and risk of all glioma as well as the risk of glioblastoma subtype in the National Institutes of Health (NIH)-AARP Diet and Health Study. The frequency of aspirin and nonaspirin NSAID use 1 year prior to baseline was ascertained using a self-administered questionnaire. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox regression models with age as the underlying time metric, adjusted for sex, race, and history of heart disease. The analysis included 302,767 individuals, with 341 incident glioma cases (264 glioblastoma). No association was observed between regular use (>2 times/wk) of aspirin and risk of glioma (HR = 1.16; 95% CI, 0.87-1.56) or glioblastoma (HR = 1.17; 95% CI, 0.83-1.64) as compared with no use. Null associations were also observed for nonaspirin NSAID use (HR for glioma = 0.90; 95% CI, 0.65-1.25 and HR for glioblastoma = 0.83; 95% CI, 0.56-1.20) as compared with no use. Our findings from this large prospective study do not support an inverse association between NSAIDs and risk of all glioma or glioblastoma.
 ...
PMID:Nonsteroidal anti-inflammatory drugs and glioma in the NIH-AARP Diet and Health Study cohort. 2188 14

Glioma, especially glioblastoma, is a leading cause of brain cancer fatality involving highly invasive and neoplastic growth. Diffusive models of glioma growth use variations of the diffusion-reaction equation in order to simulate the invasive patterns of glioma cells by approximating the spatiotemporal change of glioma cell concentration. The most advanced diffusive models take into consideration the heterogeneous velocity of glioma in gray and white matter, by using two different discrete diffusion coefficients in these areas. Moreover, by using diffusion tensor imaging (DTI), they simulate the anisotropic migration of glioma cells, which is facilitated along white fibers, assuming diffusion tensors with different diffusion coefficients along each candidate direction of growth. Our study extends this concept by fully exploiting the proportions of white and gray matter extracted by normal brain atlases, rather than discretizing diffusion coefficients. Moreover, the proportions of white and gray matter, as well as the diffusion tensors, are extracted by the respective atlases; thus, no DTI processing is needed. Finally, we applied this novel glioma growth model on real data and the results indicate that prognostication rates can be improved.
 ...
PMID:High-grade glioma diffusive modeling using statistical tissue information and diffusion tensors extracted from atlases. 2199 Mar 37

Glioblastoma is an aggressive form of brain cancer with a poor long-term prognosis. Treatment regimens for newly diagnosed disease range from surgical resection alone to surgery followed by radiotherapy with concurrent and adjuvant chemotherapy. Ongoing investigations are focused on optimization of chemotherapy by improving dosing and duration schedules and utilization of biomarkers for patient selection. Our understanding of glioblastoma tumor biology, the role of molecular signaling pathways, cellular repair mechanisms, and angiogenesis has increased greatly over the past few years, leading to the investigation of a variety of targeted therapies. In addition, advances in radiographic assessment have significantly impacted not only improvement in diagnosis, but interpretation of response to therapy. In order to effectively evaluate the clinical utility of new agents, as well as incorporate advances in radiographic assessment, changes to current clinical trial design need to be considered. This article reviews the care for newly diagnosed glioblastoma, as well as how recent findings might be incorporated into patient care.
 ...
PMID:The impact of recent data on the optimization of standards of care in newly diagnosed glioblastoma. 2207 43


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>