Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytokine transforming growth factor (TGF)-beta, by virtue of its immunosuppressive and promigratory properties, has become a major target for the experimental treatment of human malignant gliomas. Here we characterize the effects of a novel TGF-beta receptor (TGF-betaR) I kinase inhibitor, SD-208, on the growth and immunogenicity of murine SMA-560 and human LN-308 glioma cells in vitro and the growth of and immune response to intracranial SMA-560 gliomas in syngeneic VM/Dk mice in vivo. SD-208 inhibits the growth inhibition of TGF-beta-sensitive CCL64 cells mediated by recombinant TGF-beta1 or TGF-beta2 or of TGF-beta-containing glioma cell supernatant at an EC(50) of 0.1 mumol/L. SD-208 blocks autocrine and paracrine TGF-beta signaling in glioma cells as detected by the phosphorylation of Smad2 or TGF-beta reporter assays and strongly inhibits constitutive and TGF-beta-evoked migration and invasion, but not viability or proliferation. Peripheral blood lymphocytes or purified T cells, cocultured with TGF-beta-releasing LN-308 glioma cells in the presence of SD-208, exhibit enhanced lytic activity against LN-308 targets. The release of interferon gamma and tumor necrosis factor alpha by these immune effector cells is enhanced by SD-208, whereas the release of interleukin 10 is reduced. SD-208 restores the lytic activity of polyclonal natural killer cells against glioma cells in the presence of recombinant TGF-beta or of TGF-beta-containing glioma cell supernatant. The oral bioavailability of SD-208 was verified by demonstrating the inhibition of TGF-beta-induced Smad phosphorylation in spleen and brain. Systemic SD-208 treatment initiated 3 days after the implantation of SMA-560 cells into the brains of syngeneic VM/Dk mice prolongs their median survival from 18.6 to 25.1 days. Histologic analysis revealed no difference in blood vessel formation, proliferation, or apoptosis. However, animals responding to SD-208 showed an increased tumor infiltration by natural killer cells, CD8 T cells, and macrophages. These data define TGF-beta receptor I kinase inhibitors such as SD-208 as promising novel agents for the treatment of human malignant glioma and other conditions associated with pathological TGF-beta activity.
 ...
PMID:SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. 1552 Feb 2

Malignant glioma cells secrete thrombospondin-1 (TSP-1) which participates in the motility of glioma cells, and binds to cell surface alphavbeta3 and alpha3beta1 integrins, and syndecan-1. This study evaluated the amount of TSP-1 secretion from malignant glioma cells, and the expression of alphavbeta3 and alpha3beta1 integrins, and syndecan-1. The amounts of TSP-1 in the supernatants from 10 malignant glioma cell lines and eight non-glioma malignant tumor cell lines were measured by enzyme-linked immunosorbent assay. Expression of alphavbeta3 and alpha3beta1 integrins, and syndecan-1 were examined by flow cytometry. The amounts of TSP-1 secreted by malignant glioma cells were 43 to 2431 ng/l x 10(6) cells/24 h (mean +/- SD = 626 +/- 792). Seven of 10 glioma cell lines secreted more than 100 ng of TSP-1 and three of these cell lines secreted more than 1 microg. Seven of eight non-glioma cell lines secreted less than 100 ng of TSP-1. All glioma cell lines expressed alpha3beta1 integrin and syndecan-1, and seven of 10 glioma cell lines expressed alphavbeta3 integrin. Treatment of the glioma cell lines with TGF-beta2 did not change the expression of alphavbeta3 integrin. These results suggest that malignant glioma cells secrete high levels of TSP-1, which may be important in the migration of glioma cells via interactions with alphavbeta3 and alpha3beta1 integrins, and syndecan-1.
 ...
PMID:Quantification of thrombospondin-1 secretion and expression of alphavbeta3 and alpha3beta1 integrins and syndecan-1 as cell-surface receptors for thrombospondin-1 in malignant glioma cells. 1566 72

Here, we provide first evidence that long-term continuous infusion of highly purified antisense phosphorothioate oligodeoxynucleotides (S-ODN) into brain parenchyma is well tolerated and thus highly suitable for in vivo application. AP 12009 is an S-ODN for the therapy of malignant glioma. It is directed against human transforming growth factor-beta (TGF-beta2) mRNA. In the clinical setting, AP 12009 is administered intratumorally by continuous infusion directly into the brain tumor. In view of this clinical application, the focus of our data is on local toxicology studies in rabbits and monkeys to evaluate the safety of AP 12009. AP 12009 was administered either by intrathecal bolus injection into the subarachnoidal space of the lumbar region of both cynomolgus monkeys and rabbits or by continuous intraparenchymatous infusion directly into the brain tissue of rabbits. Intrathecal bolus administration of 0.1 ml of 500 microM AP 12009 showed neither clinical signs of toxicity nor macroscopically visible or histomorphologic changes. After a 7-day intraparenchymatous continuous infusion of 500 microM AP 12009 at 1 microl/h in rabbits, there was no evidence of toxicity except for local mild to moderate lymphocytic leptomeningoencephalitis. Additionally, AP 12009 showed good tolerability in safety pharmacology as well as in acute toxicity studies and 4-week subchronic toxicity studies in mice, rats, and monkeys. This favorable safety profile proves the suitability of AP 12009 for local administration in brain tumor patients from the point of view of toxicology.
 ...
PMID:Intracerebral and intrathecal infusion of the TGF-beta 2-specific antisense phosphorothioate oligonucleotide AP 12009 in rabbits and primates: toxicology and safety. 1598 24

TGF-beta overexpression is a hallmark of various malignant tumors. This is due to the pivotal role of TGF-beta as it regulates key mechanisms of tumor development, namely immunosuppression, metastasis, angiogenesis, and proliferation. We have developed a new immunotherapeutic approach for the treatment of malignant tumors based on the specific inhibition of TGF-beta2 by the antisense oligodeoxynucleotide AP 12009. After providing preclinical proof of concept, we assessed safety and efficacy of AP 12009 in clinical phase I/II open-label dose escalation studies in high-grade glioma patients. Median survival time after recurrence exceeded the up to date literature data for chemotherapy. A phase I/II study in pancreatic carcinoma and malignant melanoma is currently ongoing. Our results implicate targeted TGF-beta2 suppression as a promising therapeutic approach for malignant tumor therapy.
 ...
PMID:Targeted tumor therapy with the TGF-beta 2 antisense compound AP 12009. 1637 33

TGF-beta2 secretion by high grade gliomas has been implicated as one of the major factors contributing to tumor growth, alterations in the host immune response to tumor, and failure of gliomas to respond to current immunotherapy strategies. We hypothesized that targeted delivery and inhibition of TGF-beta2 by TGF-beta2 antisense oligonucleotides (AS-ODNs) would overcome tumor-induced immunosuppression and enhance the capacity of tumor vaccines to eradicate established brain tumors. Utilizing the mRNA sequences of TGF-beta2, specific AS-ODNs were constructed and tested for their ability to inhibit TGF-beta2 production in 9L glioma cells. The effect of combining local intracranial administration of antisense ODNs with systemic tumor vaccine was examined. Fisher 344 rats were vaccinated subcutaneously with irradiated 9L tumor cells 3 days after intracranial tumor implantation. Four days after vaccination, ODNs were administered into the tumor mass and survival was followed. ODNs delivered locally distributed widely within the brain tumor mass and inhibited TGF-beta2 expression. Survival of tumor-bearing rats treated with the combination of local antisense and systemic tumor vaccine was significantly enhanced (mean survival time (MST): 48.0 days). In contrast, MST for animals treated with nonsense plus vaccine, vaccine alone, antisense alone or PBS showed no survival advantage and no statistical differences between groups (33.5 days, 29.0 days, 37.5 days, and 31.5 days, respectively). Our data supports the hypothesis that local administration of antisense TGF-beta2 ODNs combined with systemic vaccination can increase efficacy of immunotherapy and is a novel, potentially clinically applicable, strategy for high-grade glioma treatment.
 ...
PMID:TGF-beta2 inhibition augments the effect of tumor vaccine and improves the survival of animals with pre-established brain tumors. 1694 Oct 73

Malignant gliomas are able to secrete large amounts of immunosuppressive cytokines like transforming growth factor beta 2 (TGF-beta2) and regularly escape from immune surveillance. Many strategies have been developed to induce potent anti-glioma responses, among those the use of dendritic cells (DC) as therapeutic vaccines. Here, we report that both mature DC and IL-12 secretion are necessary to overcome T-cell inhibition by TGF-beta2. Flow cytometric analyses showed that TGF-beta2 does not suppress the upregulation of MHC (major histocompatibility complex) class II molecules and the T cell stimulatory capacity of human DC that were stimulated with a strong cytokine cocktail containing tumor necrosis factor alpha (TNF-alpha), IL-1beta, IL-6 and prostaglandin E2 (PGE2). Moreover, TGF-beta2 signaling studies revealed that these cytokine-matured DC become unresponsive to TGF-beta2. Although both mature and immature DC expressed comparable amounts of the TGF-beta receptor type II, Smad2 phosphorylation and subsequent upregulation of Smad7 was inhibited in mature DC, but not immature DC. However, further analysis revealed that mature DC alone are not sufficient to mediate full T cell activation in the presence of TGF-beta2, unless IL-12 is added to the DC/T-cell coculture. Finally, we demonstrate that MHC class II expression and IL-12 secretion by DC are not disturbed by TGF-beta2 after DC stimulation with a modified maturation cocktail containing the Toll-like receptor (TLR)-ligands Poly I:C or R848, TNF-alpha, IL-1beta and INF-gamma. These data imply that mature DC retaining their capacity to produce IL-12 are of favorable use in glioma immunotherapy and suggest that TLR triggering of DC plays an important role to elicit a strong immune response in the immunosuppressive environment of malignant gliomas.
 ...
PMID:Toll-like receptor triggered dendritic cell maturation and IL-12 secretion are necessary to overcome T-cell inhibition by glioma-associated TGF-beta2. 1710 49

The transforming growth factor-beta (TGF-beta) plays a pivotal role in the pathobiology of human gliomas: during carcinogenesis, it turns from a tumor suppressor to a tumor promoter. The traditional Smad pathway and the more recently discovered MAPK pathway are the most important pathways for TGF-beta related intracellular signal transduction mediating differential pathobiological effects. In this study, we investigated the effects of TGF-beta2 and the TGF-beta2 antisense phosphorothioate oligodeoxynucleotide (PTO) AS-11 on the functionality of both the Smad and MAPK pathways in high-grade gliomas. We aimed to correlate the imbalance between the pathways with differences in the behaviour of high-grade glioma cells. Gene and protein expression studies were used to detect levels of members of the Smad and MAPK pathways under regulation of TGF-beta2 and AS-11. Proliferation and migration assays were functional readouts for effects caused by these regulating tools. Gene arrays were used to detect yet unknown regulators of these functional effects. The Smad pathway was functional in the tested cell lines. Exogenous TGF-beta2 inhibited proliferation but enhanced migration. Smad 2 mRNA expression and activation were significantly reduced by incubation with AS-11. K-ras was reduced both in gene arrays and quPCR under treatment with AS-11, but there was no influence of K-ras down-regulation on the activity of ERK. Ubiquitination-related genes also were specifically down-regulated with AS-11. Our results indicate the involvement of K-ras in TGF-beta signaling in high-grade gliomas. ERK, which is a member of the MAPK pathway, was not influenced and seems to be activated through RAS independent cascades in glioma. These results suggest that combined antagonization of the TGF-beta and MAPK pathways might be a promising approach for glioma therapy. An imbalance between these two pathways might be responsible for TGF-beta switching to a tumor promoter protein in high-grade gliomas.
 ...
PMID:An imbalance between Smad and MAPK pathways is responsible for TGF-beta tumor promoting effects in high-grade gliomas. 1720 33

Due to its immunosuppressive properties, the cytokine transforming growth factor (TGF)-beta has become a promising target in the experimental treatment of human malignant gliomas. Here, we report that the antifibrotic drug 5-methyl-1-phenyl-2-(1H)-pyridone (pirfenidone, PFD) elicits growth-inhibitory effects and reduces TGF-beta2 protein levels in human glioma cell lines. This reduction in TGF-beta2 is biologically relevant since PFD treatment reduces the growth inhibition of TGF-beta-sensitive CCL-64 cells mediated by conditioned media of glioma cells. The downregulation of TGF-beta is mediated at multiple levels. PFD leads to a reduction of TGF-beta2 mRNA levels and of the mature TGF-beta2 protein due to decreased expression and direct inhibition of the TGF-beta pro-protein convertase furin. In addition, PFD reduces the protein levels of the matrix metalloproteinase (MMP)-11, a TGF-beta target gene and furin substrate involved in carcinogenesis. These data define PFD or PFD-related agents as promising agents for human cancers associated with enhanced TGF-beta activity.
 ...
PMID:Pirfenidone inhibits TGF-beta expression in malignant glioma cells. 1723 58

Transforming growth factor-beta2 (TGF-beta2) is known to suppress the immune response to cancer cells and plays a pivotal role in tumor progression by regulating key mechanisms including proliferation, metastasis, and angiogenesis. For targeted protein suppression the TGF-beta2-specific antisense oligodeoxynucleotide AP 12009 was developed. In vitro experiments have been performed to prove specificity and efficacy of the TGF-beta2 inhibitor AP 12009 employing patient-derived malignant glioma cells as well as peripheral blood mononuclear cells (PBMCs) from patients. Clinically, the antisense compound AP 12009 was assessed in three Phase I/II-studies for the treatment of patients with recurrent or refractory malignant (high-grade) glioma WHO grade III or IV. Although the study was not primarily designed as an efficacy evaluation, prolonged survival compared to literature data and response data were observed, which are very rarely seen in this tumor indication. Two patients experienced long-lasting complete tumor remissions. These results implicate targeted TGF-beta2-suppression using AP 12009 as a promising novel approach for malignant gliomas and other highly aggressive, TGF-beta-2-overexpressing tumors.
 ...
PMID:Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies. 1763 24

Glioma-initiating cells (GICs) are responsible for the initiation and recurrence of gliomas. Here, we identify a molecular mechanism that regulates the self-renewal capacity of patient-derived GICs. We show that TGF-beta and LIF induce the self-renewal capacity and prevent the differentiation of GICs. TGF-beta induces the self-renewal capacity of GICs, but not of normal human neuroprogenitors, through the Smad-dependent induction of LIF and the subsequent activation of the JAK-STAT pathway. The effect of TGF-beta and LIF on GICs promotes oncogenesis in vivo. Some human gliomas express high levels of LIF that correlate with high expression of TGF-beta2 and neuroprogenitor cell markers. Our results show that TGF-beta and LIF have an essential role in the regulation of GICs in human glioblastoma.
 ...
PMID:TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. 1934 22


<< Previous 1 2 3 Next >>