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

The purpose of this study was to characterize the effects of sodium 4-phenylbutyrate (phenylbutyrate) on the proliferation, morphology, migration and invasiveness of malignant glioma cells in vitro. Phenylbutyrate is a novel differentiating and cytotoxic compound used clinically with low toxicity in the treatment of beta-thalassemia, sickle cell anemia and urea cycle disorders. Preliminary clinical trials testing phenylbutyrate as an anti-cancer agent have included patients with malignant glioma. However, little information is available regarding the effects of phenylbutyrate on glioma cells, particularly with respect to the expression of genes important in the pathogenesis of glial malignancy. In experiments reported here, glioma cell lines and explant cells from a tumor patient were exposed to 2, 4 and 8 mM phenylbutyrate and compared to untreated control cells. The effect on cellular proliferation was assessed using cell counts and DNA flow cytometry. Changes in morphology were evaluated using vimentin staining. Scratch and Matrigel assays were performed to assess changes in cellular migration and invasiveness. Finally, Northern blot analysis was used to study c-myc and urokinase expression. Phenylbutyrate was found to have dose-dependent inhibitory effects on glioma cell proliferation, morphology, migration, invasiveness and c-myc and urokinase expression. Mean growth-inhibitory (IC50) phenylbutyrate concentrations ranged from 0.5 mM for T98G cells to 5.0 mM for explant cells. Phenylbutyrate treatment reduced % S phase cells, increased % G0/G1 cells, and produced morphologic changes consistent with induction of differentiation. 24 hours of treatment with 4 mM phenylbutyrate resulted in a 50% reduction in migration and invasiveness. Northern blots showed a decrease in urokinase and c-myc expression at non-cytotoxic doses. We conclude that phenylbutyrate is a promising candidate compound for treating patients with malignant glioma.
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PMID:Inhibitory effects of phenylbutyrate on the proliferation, morphology, migration and invasiveness of malignant glioma cells. 952 87

Several studies have reported on structural abnormalities, decreased myelination and oligodendrocyte dysfunction in post-mortem brains from schizophrenic patients. Glia-derived cholesterol is essential for both myelination and synaptogenesis in the CNS. Lipogenesis and myelin synthesis are thus interesting etiological candidate targets in schizophrenia. Using a microarray approach, we here demonstrate that the antipsychotic drugs clozapine and haloperidol upregulate several genes involved in cholesterol and fatty acid biosynthesis in cultured human glioma cells, including HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), HMGCS1 (3-hydroxy-3-methylglutaryl-coenzyme A synthase-1), FASN (fatty acid synthase) and SCD (stearoyl-CoA desaturase). The changes in gene expression were followed by enhanced HMGCR-enzyme activity and elevated cellular levels of cholesterol and triglycerides. The upregulated genes are all known to be controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We show that clozapine and haloperidol both activate the SREBP system. The antipsychotic-induced SREBP-mediated increase in glial cell lipogenesis could represent a novel mechanism of action, and may also be relevant for the metabolic side effects of antipsychotics.
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PMID:Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action? 1602 36

Red blood cells from patients with sickle cell disease will sickle under conditions of hypoxemia and acidosis which is a similar milieu found in malignant tumors. While control of tumor angiogenesis has long been a goal of cancer therapy, selective occlusion of tumor blood supply may be achieved by transfusion of sickle cells into patients who suffer metastatic cancer. Although this potential therapy has not been previously reported in the medical literature, the concept may have been elusive to medical mainstream thinking because it requires transfusion of diseased cells. For this therapy to be effective, other environmental factors may need to be manipulated such inducing mild hypoxemia or hypercarbia (respiratory acidosis) to induce red cell sickling. Preliminary evidence supportive of this therapeutic approach to cancer treatment is provided by case evidence that sickle cell occlusion of a malignant brain tumor (glioma) produced tumor necrosis. Also sickle cells have been successfully transfused into primates. Furthermore, donor blood is crossmatched and transfused into patients suffering from sickle cell disease regularly in clinics and this procedure is associated with acceptable morbidity. Most importantly, animal models of sickle cell disease and cancer currently exist, and this theory could be tried with available technologies including ultrasound detection of vaso-occlusion. While the proposed therapy may not cure metastatic cancer, this treatment could prove useful for decreasing the size and perhaps the pain from metastatic tumor burden. Therefore, it is hypothesized that ABO Rh compatible crossmatched sickle cells transfused into patients who suffer metastatic cancer under controlled conditions of blood oxygenation and pH will selectively produce vaso-occlusive infarcts in malignant tumors and be a useful therapy. The author hopes for further investigations.
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PMID:Transfusion of sickle cells may be a therapeutic option for patients suffering metastatic disease. 2044 56

Therapy resistance and tumor recurrence are often linked to a small refractory and highly tumorigenic subpopulation of neoplastic cells, known as cancer stem cells (CSCs). A putative marker of CSCs is CD133 (prominin-1). We have previously described a CD133-targeted oncolytic measles virus (MV-CD133) as a promising approach to specifically eliminate CD133-positive tumor cells. Selectivity was introduced at the level of cell entry by an engineered MV hemagglutinin (H). The H protein was blinded for its native receptors and displayed a CD133-specific single-chain antibody fragment (scFv) as targeting domain. Interestingly, MV-CD133 was more active in killing CD133-positive tumors than the unmodified MV-NSe despite being highly selective for its target cells. To further enhance the antitumoral activity of MV-CD133, we here pursued arming technologies, receptor extension, and chimeras between MV-CD133 and vesicular stomatitis virus (VSV). All newly generated viruses including VSV-CD133 were highly selective in eliminating CD133-positive cells. MV-CD46/CD133 killed in addition CD133-negative cells being positive for the MV receptors. In an orthotopic glioma model, MV-CD46/CD133 and MVSCD-CD133, which encodes the super cytosine deaminase, were most effective. Notably, VSV-CD133 caused fatal neurotoxicity in this tumor model. Use of CD133 as receptor could be excluded as being causative. In a subcutaneous tumor model of hepatocellular cancer, VSV-CD133 revealed the most potent oncolytic activity and also significantly prolonged survival of the mice when injected intravenously. Compared to MV-CD133, VSV-CD133 infected a more than 104-fold larger area of the tumor within the same time period. Our data not only suggest new concepts and approaches toward enhancing the oncolytic activity of CD133-targeted oncolytic viruses but also raise awareness about careful toxicity testing of novel virus types.
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PMID:Enhancing the Oncolytic Activity of CD133-Targeted Measles Virus: Receptor Extension or Chimerism with Vesicular Stomatitis Virus Are Most Effective. 2869 8