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)

Despite advancements in therapeutic regimens, the prognosis remains poor for patients with malignant gliomas. Specificity has been an elusive goal for current modalities, but immunotherapy has emerged as a potential means of designing more tumor-specific treatments. Dendritic cells (DC) are the specialized antigen presenting cells of the immune system and have served now as a platform for therapeutic immunizations against such cancers as lymphoma, multiple myeloma, melanoma, prostate cancer, renal cell carcinoma, non-small cell lung carcinoma, colon cancer, and even malignant gliomas. DC-based immunizations offer a number of advantages over traditional immunotherapeutic approaches to brain tumors, approaches that have proved promising despite concerns over central nervous system immune privilege and glioma-mediated immunosuppression. The future success of clinical trials will depend on the optimization and standardizing of procedures for DC generation, loading, and administration.
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PMID:The history, evolution, and clinical use of dendritic cell-based immunization strategies in the therapy of brain tumors. 1295 97

Thalidomide, an oral agent with antiangiogenic and immunomodulatory properties, is being investigated extensively in the management of advanced cancer. Multiple studies with large numbers of patients have confirmed that this drug has significant activity in multiple myeloma. Some patients with myelofibrosis or myeodysplatic syndromes may reduce their need for transfusions after thalidomide treatment. The activity of thalidomide in solid tumors is less prominent. Studies in Kaposi's sarcoma, malignant melanoma, renal cell carcinoma and prostate cancer appear more promising especially when thalidomide is combined with biological agents or with chemotherapy. Limited activity was demonstrated in patients with glioma, while thalidomide appears to be inactive in patients with head and neck cancer, breast or ovarian cancer.
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PMID:Thalidomide in cancer medicine. 1527 53

Interferon-beta gene therapy for cancer is the first such protocol developed in Japan. Here we describe the development process of our interferon-beta gene therapy from basic research to clinical application. Interestingly, the biological and biochemical characteristics of interferon-beta gene therapy through transfer of the interferon-beta gene into tumor cells by means of cationic liposomes differed from those of conventional interferon-beta protein therapy. Interferon-beta gene transfer could induce apoptosis in interferon-beta protein-resistant tumor cells, such as glioma, melanoma, and renal cell carcinoma. Induction of apoptosis was related to the level of intracellular mRNA of interferon-beta, prolongation of the phosphorylation time of molecules in the interferon-beta signal transduction pathway, such as JAK1, Trk2, and STAT1, and activation of DNase gamma. In our preclinical study we developed lyophilized cationic liposomes containing interferon-beta gene (gene drug) for clinical use and confirmed their safety. Thereafter, we performed a pilot clinical trial in patients with malignant glioma and confirmed the safety and effectiveness of this interferon-beta gene therapy. In this review we also comment on the status of gene therapy regulation in Japan. Interferon-beta gene therapy is expected to become widely available for clinical use in cancer patients, and this new strategy might be extended to molecular targeting therapy, or used in combination with cell therapy or other therapies.
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PMID:Interferon-beta gene therapy for cancer: basic research to clinical application. 1554 2

Deregulated phosphatidylinositol 3-kinase (PI3K) signaling pathway is widely implicated in tumor growth and resistance to chemotherapy. While a strong rationale exists for pharmacological targeting of PI3K, only a few proof-of-principle in vivo efficacy studies are currently available. PWT-458, pegylated-17-hydroxywortmannin, is a novel and highly potent inhibitor of PI3K in animal models. Upon in vivo cleavage of its poly(ethyleneglycol) (PEG), PWT-458 releases its active moiety 17-hydroxywortmannin (17-HWT), the most potent inhibitor in its class. Here we show that a single intravenous injection of PWT-458 rapidly inhibited PI3K signaling, as measured by a complete loss of AKT (Ser-473) phosphorylation in xenograft tumors grown in nude mice. Following a daily X5 dosing regimen, PWT-458 demonstrated single-agent antitumor activity in nude mouse xenograft models of U87MG glioma, nonsmall cell lung cancer (NSCLC) A549, and renal cell carcinoma (RCC) A498. Efficacious doses ranged from 0.5 mg/kg to 10 mg/kg, achieving a superior therapeutic index over 17-HWT. PWT-458 augmented anticancer efficacy of a suboptimal dose of paclitaxel against A549 and U87MG tumors. Combination treatment of PWT-458 and an mTOR inhibitor, Pegylated-Rapamycin (Peg-Rapa), resulted in an enhanced antitumor efficacy in U87MG. Finally, PWT-458 in combination with interferon-alpha (Intron-A) caused a dramatic regression of RCC A498, which was not achieved by either agent alone. These studies identify PWT-458 as an effective anticancer agent and provide strong proof-of-principle for targeting the PI3K pathway as novel anticancer therapy.
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PMID:PWT-458, a novel pegylated-17-hydroxywortmannin, inhibits phosphatidylinositol 3-kinase signaling and suppresses growth of solid tumors. 1590 1

Endothelial cell phenotypes are differentially regulated between different sites of the vascular tree. We tested the hypothesis that endocan, a novel soluble dermatan sulfate proteoglycan, is differentially expressed in the intact endothelium and that site-specific expression is mediated by signals in the local microenvironment. Using a combination of Northern blot analyses, Taqman RT-PCR, and in situ hybridizations, endocan was shown to be preferentially expressed in the endothelial lining of tumor xenografts, including human non-small cell lung cancer, rat glioma, and human renal cell carcinoma. In contrast, endocan mRNA was expressed at low levels in embryos between E4.5 and E18.5. Under in vitro conditions, endocan expression in human umbilical vein endothelial cells (HUVEC) was upregulated by tumor cell-conditioned medium, an effect that was inhibited by the addition of neutralizing antibody to vascular endothelial growth factor (VEGF). Moreover, treatment of HUVEC with VEGF resulted in a dose- and time-dependent increase in endocan mRNA. The results suggest that endocan is preferentially expressed in tumor endothelium in vivo and that its expression is regulated by tumor-derived factors.
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PMID:Vascular endocan is preferentially expressed in tumor endothelium. 1695 26

This study was undertaken to characterize preclinical cytotoxic interactions for human malignancies between the multikinase inhibitor sorafenib (BAY 43-9006) and proteasome inhibitors bortezomib or MG132. Multiple tumor cell lines of varying histiotypes, including A549 (lung adenocarcinoma), 786-O (renal cell carcinoma), HeLa (cervical carcinoma), MDA-MB-231 (breast), K562 (chronic myelogenous leukemia), Jurkat (acute T-cell leukemia), MEC-2 (B-chronic lymphocytic leukemia), and U251 and D37 (glioma), as well as cells derived from primary human glioma tumors that are likely a more clinically relevant model were treated with sorafenib or bortezomib alone or in combination. Sorafenib and bortezomib synergistically induced a marked increase in mitochondrial injury and apoptosis, reflected by cytochrome c release, caspase-3 cleavage, and poly(ADP-ribose) polymerase degradation in a broad range of solid tumor and leukemia cell lines. These findings were accompanied by several biochemical changes, including decreased phosphorylation of vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor-beta, and Akt and increased phosphorylation of stress-related c-Jun NH2-terminal kinase (JNK). Inhibition of Akt was required for synergism, as a constitutively active Akt protected cells against apoptosis induced by the combination. Alternatively, the JNK inhibitor SP600125 could also protect cells from apoptosis induced by the combination, indicating that both inhibition of Akt and activation of JNK were required for the synergism. These findings show that sorafenib interacts synergistically with bortezomib to induce apoptosis in a broad spectrum of neoplastic cell lines and show an important role for the Akt and JNK pathways in mediating synergism. Further clinical development of this combination seems warranted.
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PMID:Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. 1698 72

Hypoxia-inducible factor-1alpha (HIF-1alpha) has been implicated in the transcriptional regulation of the telomerase reverse transcriptase (hTERT) gene expression and telomerase activity, essential elements for cellular immortalization and transformation. However, controversial results were obtained in different studies. Moreover, it is totally unclear whether HIF-2alpha, the paralog of HIF-1alpha, plays a role in regulating hTERT expression. In the present study, we found that hypoxic treatment enhanced hTERT mRNA expression and telomerase activity in three renal cell carcinoma (RCC) cell lines with different genetic backgrounds. Both HIF-1alpha and HIF-2alpha were capable of significantly increasing the hTERT promoter activity in these cells. Moreover, depleting HIF-2alpha led to a down-regulation of hTERT mRNA level in RCC A498 cells expressing constitutive HIF-2alpha. It was found that HIF-2alpha bound to the hTERT proximal promoter and enhanced the recruitment of the histone acetyltransferase p300 and histone H3 acetylation locally in A498 cells treated with hypoxia. Increased levels of hTERT mRNA were observed in two of three hypoxia-treated malignant glioma cell lines. However, HIF-1alpha stimulated whereas HIF-2alpha inhibited the hTERT promoter activity in these glioma cell lines. Ectopic expression of HIF-2alpha resulted in diminished hTERT expression in glioma cells. Collectively, HIF-1alpha activates hTERT and telomerase expression in both RCC and glioma cells, and HIF-2alpha enhances hTERT expression in RCC cells, whereas it represses the hTERT transcription in glioma cells. These findings reveal a complex relationship between HIF-1alpha/2alpha and hTERT/telomerase expression in malignant cells, which may have both biological and clinical implications.
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PMID:The opposing effect of hypoxia-inducible factor-2alpha on expression of telomerase reverse transcriptase. 1769 5

To exert a therapeutic effect, adoptively transferred tumor-specific CTLs must traffic to sites of tumor burden, exit the circulation, and infiltrate the tumor microenvironment. In this study, we examine the ability of adoptively transferred human CTL to traffic to tumors with disparate chemokine secretion profiles independent of tumor Ag recognition. Using a combination of in vivo tumor tropism studies and in vitro biophotonic chemotaxis assays, we observed that cell lines derived from glioma, medulloblastoma, and renal cell carcinoma efficiently chemoattracted ex vivo-expanded primary human T cells. We compared the chemokines secreted by tumor cell lines with high chemotactic activity with those that failed to elicit T cell chemotaxis (Daudi lymphoma, 10HTB neuroblastoma, and A2058 melanoma cells) and found a correlation between tumor-derived production of MCP-1/CCL2 (> or =10 ng/ml) and T cell chemotaxis. Chemokine immunodepletion studies confirmed that tumor-derived MCP-1 elicits effector T cell chemotaxis. Moreover, MCP-1 is sufficient for in vivo T cell tumor tropism as evidenced by the selective accumulation of i.v. administered firefly luciferase-expressing T cells in intracerebral xenografts of tumor transfectants secreting MCP-1. These studies suggest that the capacity of adoptively transferred T cells to home to tumors may be, in part, dictated by the species and amounts of tumor-derived chemokines, in particular MCP-1.
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PMID:Tumor-derived chemokine MCP-1/CCL2 is sufficient for mediating tumor tropism of adoptively transferred T cells. 1770 50

We have shown previously that high-affinity receptors for interleukin-13 (IL-13Ralpha2) are overexpressed on a variety of solid cancer cells, diseased fibroblasts, and other cells, and a chimeric fusion protein composed of human IL-13 and mutated Pseudomonas exotoxin (IL-13-PE38) is highly and specifically cytotoxic to these cells in vitro and in vivo. To improve the specificity for the target, we isolated specific antibodies against IL-13Ralpha2 from human single-chain Fv (scFv) antibody phage library and developed immunotoxin by selecting two high-affinity clones of scFv and fused to PE. The fusion chimeric gene was expressed in Escherichia coli, and highly purified IL-13R-specific immunotoxin, termed anti-IL-13Ralpha2(scFv)-PE38, was tested for its cytotoxicity. This molecule was highly cytotoxic to U251 glioma and PM-RCC renal cell carcinoma cell lines in vitro. The cytotoxic activity was neutralized by purified extracellular domain of IL-13Ralpha2 but not by IL-13, indicating that cytotoxic activity is specific. Anti-IL-13Ralpha2(scFv)-PE38 showed significant antitumor activity in immunodeficient mice with s.c. glioma tumors. Both i.p. and i.t. routes of administration showed antitumor activity in a dose-dependent manner. The maximum tolerated dose of anti-IL-13Ralpha2(scFv)-PE38 was 200 microg/kg i.p. twice daily for 5 days. These results indicate that anti-IL-13Ralpha2(scFv)-PE38 is a highly selective therapeutic agent for cancer therapy and should be further tested in animal models of human cancer.
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PMID:Targeting IL-13Ralpha2-positive cancer with a novel recombinant immunotoxin composed of a single-chain antibody and mutated Pseudomonas exotoxin. 1856 28

We describe herein a malignant glioma arising at the site of the resected hemangioblastoma after irradiation in a patient with von Hippel-Lindau disease (VHL). The patient was a 25 year-old male with multiple hemangioblastomas at the cerebellum and spinal cord, multiple pancreatic cysts and a renal cell carcinoma; he was diagnosed as having VHL disease. The largest hemangioblastoma at the right cerebellar hemisphere was completely removed, and he received high-dose irradiation postoperatively. The tumor recurred at the same site 7 years later, which was a malignant glioma with no evidence of hemangioblastoma. The malignant glioma showed molecular genetic profiles of radiation-induced tumors because of its diffuse p53 immunostaining and the loss of p16 immunoreactivity. The genetic study to find the loss of heterozygosity (LOH) of VHL gene revealed that only the cerebellar hemangioblastoma showed allelic losses for the gene. To the best of our knowledge, this report is the first to show a malignant glioma that developed in a patient with VHL disease after radiation therapy at the site of an excised hemangioblastoma. This report also suggests that radiation therapy should be performed very carefully in VHL patients with hemangioblastomas.
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PMID:Malignant glioma arising at the site of an excised cerebellar hemangioblastoma after irradiation in a von Hippel-Lindau disease patient. 1971 9


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