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)

Neural precursor cells (NPCs) populate the embryonic ventricular zone and persist in the subependymal zone of the adult brain. We hypothesized that hereditary and/or acquired mutations in apoptosis-associated genes, such as p53 and caspases, may protect NPCs from DNA damage-induced death and predispose them to subsequent neoplastic transformation. To test this hypothesis, we exposed NPCs from wild-type and targeted gene-disrupted mouse embryos (p53, caspase-9, caspase-3, and bax mutants) to ethyl-nitrosourea (ENU), a known DNA mutagen and neural carcinogen, and measured NPC viability. We found that ENU produced caspase-3 activation and apoptotic NPC death 6-24 h after administration both in vivo and in vitro. This effect was critically dependent on p53 and caspase-9 expression. The long-term effect of intrauterine ENU exposure was examined in control and p53-deficient mice. High grade glial tumors were found in 60% of p53(-/-) young adult mice exposed to ENU on gestational day 12.5 but not in p53(+/-) or p53(+/+) littermates or in untreated p53-deficient mice. All the tumors were located supratentorially and possessed strong immunoreactivity for glial fibrillary acidic protein and the anti-apoptotic molecule Bcl-X(L). These results suggest that intrauterine exposure of NPCs to certain DNA damaging agents may synergistically interact with specific genetic abnormalities (e.g. p53 deficiency) to produce glial neoplasms in the adult brain.
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PMID:Neural precursor cell apoptosis and glial tumorigenesis following transplacental ethyl-nitrosourea exposure. 1178 43

Identification of patients with a low grade glioma with a long-term recurrence-free survival is of clinical value as radiotherapy can be postponed until recurrence. The recurring glioma may increase in malignancy compared to the original tumor, which is possibly related to radiotherapy. We studied proliferation by counting mitotic figures and by MIB-1 labeling, apoptosis by TUNEL and expression of proteins related to cell cycle regulation by immunohistochemical analysis of p53, p21, bcl-2 and bax expression in 48 low grade gliomas. Astrocytomas (A, n = 14) and oligodendrogliomas (O, n = 4) with a recurrence-free survival of more than 9 years after surgery had a signficantly lower p53 index compared to A (n = 18) and O (n = 12) with a histopathologically documented recurrence. Additionally, the recurrence-free A had a higher p21 index. No significant differences were observed in MIB-LI, TUNEL-LI, bcl-2 and bax expression. Initially low grade gliomas and their corresponding recurrences were compared (n = 30). In the gliomas without radiotherapy (n = 15), no differences in mitotic rate, TUNEL-LI, p53, p21, bcl-2 and bax expression were found between primary tumors and their recurrences. Only MIB-LI was higher in the recurrent tumors. In the gliomas with radiotherapy (n = 15) no differences were detected in these parameters between the original tumor and the recurrent tumor except for a higher number of mitoses in the recurrent tumors. We conclude that low grade gliomas with a long-term recurrence-free survival were characterized by a low p53 protein expression and, in the case of A, a higher p21 index. We found no evidence that radiotherapy is involved in changes of proliferation, apoptosis or expression of proteins related to cell cycle regulation in recurring gliomas.
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PMID:Proliferation and apoptosis in long-term surviving low grade gliomas in relation to radiotherapy. 1216 88

Gliomas are highly resistant to any kind of treatment. Multiple genetic abnormalities exist in gliomas indicating that effective gene therapy should be directed towards replacement of multiple rather than single genes. Bax is a protein of the Bcl-2 family that promotes apoptosis and functions as a tumor suppressor gene. The E2F family of transcription factors plays a pivotal role in the regulation of cell-cycle and cell-death related genes in gliomas. We examined the therapeutic potential of the simultaneous transfer of Bax and E2F molecules (1, 2 or 4) to gliomas. We used first generation E1A-deleted adenoviral vectors to transduce the E2Fs and Bax cDNAs. The recombinant adenoviral vector encoding bax uses the inducible Cre-loxP system to transduce the protein expression. Western blot analysis and immunofluorescence assays demonstrated high level of expression of the exogenous proteins. Trypan blue cell viability assays and flow cytometric cell-cycle analysis demonstrated an additive effect of these molecules to induce cell death via apoptosis. Western blot analysis showed that the ectopic expression of E2F-1 decreased the level of expression of Bax. These results indicate that E2F-1 and Bax have an additive anti-glioma effect when expressed simultaneously at high levels. Our data also suggest that Bax is not involved in the E2F-1-mediated apoptosis.
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PMID:Overexpression of E2F-1 leads to bax-independent cell death in human glioma cells. 1237 Jul 49

Successful therapy of high-grade tumors of the brain is likely to require a combination of new therapeutic approaches. The major goal of the present study was to construct a plasmid-based bax gene vector (pGL1-Bax) and evaluate its expression in vitro and in vivo using athymic mice with subcutaneously growing C6 glioma. Preliminary experiments of efficacy and safety were also performed using pGL1-Bax alone and in combination with previously constructed pGL1-TNF-alpha, as well as with radiation. pGL1-Bax was expressed by C6 cells and was correlated with apoptosis, indicating that the construct and the bax protein were functional. Although intratumoral injections of pGL1-Bax alone, up to total doses of 450 micro g, did not significantly affect tumor growth, consistently smaller tumors were obtained when pGL1-TNF-alpha plus pGL1-Bax were injected 16-18 hr prior to tumor irradiation. Furthermore, in mice with two tumors, one treated and one untreated, progression of the untreated tumor was delayed in the animals receiving all three modalities. No prohibitive toxicities were noted, based on mouse body weights and in vitro assays of blood and spleen. Significant increases in spleen mass, total leukocyte counts, percentage of granulocytes, spontaneous blastogenesis, and CD71-expressing B cells were primarily associated with tumor presence and not treatment type. Overall, the results are promising and suggest that TNF-alpha/Bax gene therapy may be beneficial against highly malignant tumors of the brain. To our knowledge, this is the first report of bax gene therapy used together with radiation in an in vivo glioma model.
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PMID:Evaluation of TNF-alpha/Bax gene therapy and radiation against C6 glioma xenografts. 1262 53

The topoisomerase-I inhibitor irinotecan (CPT-11) is currently used in Phase I/II trials for the treatment of patients with recurrent malignant gliomas. Protein kinase C (PKC) inhibitors such as high-dose tamoxifen and hypericin also have been used in the treatment of malignant gliomas. The current study examined the role of PKC inhibitors as chemosensitizers for CPT-11 and their proposed mechanism of action. Two glioma cell lines (A-172 and U-87) and one primary glioma cell culture (LA-567) were used. Proliferation ((3)H-thymidine) and cytotoxicity (methylthiotetrazole) studies were performed using CPT-11 (0-100 microM) alone, 7-ethyl-10-hydroxy camptothecin (SN-38) (0-1000 nM) alone or in the presence of a PKC inhibitor, tamoxifen (10 microM), hypericin (10 microM), calphositin C (400 nM), or staurosporine (10 nM). The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL) assay was used to determine apoptosis as the mechanism of cytotoxicity; alterations in bcl-2 and bax expression were determined using Western blot analysis. Conversion of CPT-11 to SN-38 by glioma cells was determined using high-performance liquid chromatography (HPLC) analysis. Increasing CPT-11 and SN-38 concentrations induced cytotoxic morphologic changes, decreased proliferation, and increased cytotoxicity on all glioma cell lines tested. These changes were increased in the presence of a PKC inhibitor. The mechanism of the cytotoxicity was determined to be apoptosis by the TUNEL assay. The combination of a PKC inhibitor with CPT-11 or SN-38 led to decreased expression of the antiapoptotic protein bcl-2, and increased expression of the proapoptotic protein bax. HPLC analysis demonstrated conversion of CPT-11 to SN-38 by glioma cells. A combination of CPT-11 or SN-38 with a PKC inhibitor was found to lead to a decrease in proliferation and an increase in apoptosis in malignant glioma cells. The induction of apoptosis was secondary to a decrease in bcl-2 and an increase in bax expression. Glioma cells are capable of converting CPT-11 to SN-38 by intrinsic tumor carboxylesterases.
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PMID:Combination therapy with irinotecan and protein kinase C inhibitors in malignant glioma. 1271 58

High-grade tumors of the brain remain virtually incurable with current therapeutic regimens, new approaches to augment existing therapies need to be explored. The major goal of this pilot study was to evaluate the feasibility of gene therapy using plasmid DNA encoding tumor necrosis factor-alpha and bax together with proton radiation in an immunocompetent animal model with orthotopic brain tumor. C6 glioma cells were stereotactically implanted into the left hemibrain of Wistar rats (day 0). On day 5, the appropriate groups received intratumoral pGL1-TNF-a and pGL1-Bax (10 microg each), parental plasmid pWS4 (20 microg), or PBS. Hemibrain proton irradiation (10 Gy, 90 MeV, single fraction) was delivered 18-20 hr later. Rats were euthanized when signs of illness appeared. In addition, a subset of animals from each group was euthanized on day 9 for immune and other assays. By day 9, 25%, 20%, and 10% of rats treated with PBS, pWS4, or pGL1-TNF-alpha/pGL1-Bax, respectively, had been euthanized due to weight loss or other signs of illness, whereas all rats treated with pGL1-TNF-alpha/pGL1-Bax + radiation or radiation alone were healthy (P<0.05). At this same time, the pGL1-TNF-alpha/pGL1-Bax + radiation group had significantly elevated lymphocyte percentages (P<0.005 or less) and a relatively high level of lymphocytic infiltrate within tumors. Although the rats treated with pGL1-TNF-alpha/pGL1-Bax had the highest levels of activated T helper (CD4+/CD71+) and T cytotoxic (CD8+/CD71+) cells, the values were not significantly different compared to the pWS4-injected control group. Splenocytes in all tumor cell-injected groups had higher mean values for DNA and protein synthesis compared to the non-tumor cell injected control group, whereas oxygen radical production by phagocytes was consistently higher in groups injected with plasmid or treated with radiation. Body, hemibrain, and spleen masses, white blood cell, red blood cell and platelet counts, hemoglobin, hematocrit, and transforming growth factor-beta1 levels in plasma were similar among groups. The results demonstrate that treatment with pGL1-TNF-alpha/pGL1-Bax combined with proton hemibrain irradiation is safe under the conditions used. Overall, these data support further investigation of this unique combination therapy.
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PMID:Proton radiation and TNF-alpha/Bax gene therapy for orthotopic C6 brain tumor in Wistar rats. 1505 28

To clarify the molecular basis of the cytoprotective properties of immunophilin ligands (IPLs), the anti-apoptotic effects of IPLs were determined in human glioma U251 cells. GPI1046 and V10367, non-immunosuppressive IPLs (NI-IPLs), as well as FK506, an immunosuppressive IPL (I-IPL), had cytoprotective effects against hydrogen peroxide (H20O)-induced apoptotic cell death in U251 cells. H2O2 increased both the ratio of bax/bcl-2 and the p53 mRNA expression. However, pre-treatment with FK506 and V10367 significantly prevented any increase in this ratio or p53 mRNA expression. GPI1046 also reduced the ratio of bax/bcl-2 to the normal level. In addition, H2O2 significantly increased activities of all three caspases, caspase-3, caspase-8, and caspase-9, in comparison with non-H2O2 controls. However, FK506 prevented the increase of these caspase activities. On the other hand, it is well-known that glutathione (GSH) and neurotrophic factor (NTF) is related to the induction of apoptosis in neuronal cells. In U251 cells, FK506, GPI1046 and V10367 had GSH-activating and NTF-activating effects. Thus, the immunosuppressive effect is not essential for the cytoprotective properties of IPLs, and IPLs have multiple beneficial properties such as the anti-apoptotic effect, GSH-activating effect, and NTF-activating effect, although the anti-apoptotic effect of NI-IPLs is independent of the regulation of apoptotic activators such as caspase-3.
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PMID:Molecular basis of anti-apoptotic effect of immunophilin ligands on hydrogen peroxide-induced apoptosis in human glioma cells. 1526 Jan 30

Betulinic acid (BA) is a pentacyclic triterpene found in many plant species, among others in the bark of white birch Betula alba. BA was reported to display a wide range of biological effects, including antiviral, antiparasitic, antibacterial and anti-inflammatory activities, and in particular to inhibit growth of cancer cells. The aim of the study was further in vitro characterization of BA anticancer activity. In this study, we demonstrated a remarkable antiproliferative effect of BA in all tested tumor cell cultures including neuroblastoma, rabdomyosarcoma-medulloblastoma, glioma, thyroid, breast, lung and colon carcinoma, leukemia and multiple myeloma, as well as in primary cultures isolated from ovarian carcinoma, cervical carcinoma and glioblastoma multiforme. Furthermore, we have shown that BA decreased cancer cell motility and induced apoptotic cell death. We also observed decrease of bcl2 and cyclin D1 genes expression, and increase of bax gene expression after betulinic acid treatment. These findings demonstrate the anticancer potential of betulinic acid and suggest that it may be taken into account as a supportive agent in the treatment of cancers with different tissue origin.
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PMID:Betulinic acid decreases expression of bcl-2 and cyclin D1, inhibits proliferation, migration and induces apoptosis in cancer cells. 1696 20

Genes known to be involved in the regulation of apoptosis include members of the bcl-2 gene family, such as inhibitors of apoptosis (bcl-2 and bcl-xl) and promotors of apoptosis (bax). The authors investigated a potential approach for the treatment of malignant gliomas by using a gene transfection technique to manipulate the level of an intracellular protein involved in the control of apoptosis. The authors transfected the murine bax gene, which had been cloned into a mammalian expression vector, into the C6 rat glioma cell line. Overexpression of the bax gene resulted in a decreased growth rate (average doubling time of 32.96 hours compared with 22.49 hours for untransfected C6, and 23.11 hours for clones transfected with pcDNA3 only), which may be caused, in part, by an increased rate of spontaneous apoptosis (0.77 +/- 0.15% compared with 0.42 +/- 0.08% for the vector-only transfected C6 cell line; p = 0.038, two-tailed Student's t-test). Treatment with 1 microM of cytosine arabinoside (ara-C) resulted in significantly more cells undergoing apoptosis in the cell line overexpressing bax than in the vector-only control cell line (23.57 +/- 2.6% compared with 5.3 +/- 0.7% terminal deoxynucleotidyl transferase--mediated biotinylated--deoxyuridine triphosphate nick-end labeling technique-positive cells; p = 0.007). Furthermore, measurements of growth curves obtained immediately after treatment with 0.5 microM ara-C demonstrated a prolonged growth arrest of at least 6 days in the cell line overexpressing bax. These results can be used collectively to argue that overexpression of bax results in increased sensitivity of C6 cells to ara-C and that increasing bax expression may be a useful strategy, in general, for increasing the sensitivity of gliomas to antineoplastic treatments.
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PMID:Transfection of C6 glioma cells with the bax gene and increased sensitivity to treatment with cytosine arabinoside. 1720 79

The AT specific minor grove DNA binding ligands bisbenzimidazole derivatives like hoechst-33342 and hoechst-33258 which scavenge free radicals and stabilize macromolecular structure have been shown to afford radioprotection by reducing the induction of DNA damage. However, their ability to inhibit topoisomerases I & II, which play important roles in damage response pathways including DNA repair can enhance radiation damage under certain conditions. Since pool sizes of the topoisomerases differ not only between normal and tumor cells, but also among different tumors, it is anticipated that radiosensitization by hoechst-33342 can vary among tumors. The present studies were, therefore, undertaken to verify this proposition in human glioma (BMG-1 &U-87) and squamous carcinoma (4197 &4451) cell lines which differ in their biological behavior (ploidy, p53, cyclins, bcl, bax etc). Isotoxic concentrations of hoechst-33342 (IC50 i.e producing 50% cell kill) administered immediately following irradiation resulted in the radiosensitization of all cell lines, with a 4&7 fold increase in the cell death (loss of clonogenic cell survival) in U-87&BMG-1 and a 3 fold increase in 4197 &4451 cells. Growth inhibition and increase in cytogenetic damage (micronuclei formation) as well as delayed apoptosis observed under these conditions corroborated well with the enhanced cell death. The ligand induced a significant cell cycle delay, particularly in the late S and G2 phases of BMG-1, U-87 and 4197 cells, while no significant changes could be observed in 4451 cells. Higher endogenous levels of cyclin B1 found in both the glioma cell lines, was enhanced further by the ligand as compared to the squamous carcinoma cells. These results clearly demonstrate that the radiosensitizing effects of the ligand are indeed heterogeneous among different human tumor cell lines. The radiaosensitization is p53 independent and accompanied by enhanced mitotic death (linked to cytogenetic damage) as well as induction of cyclin B1 mediated apoptosis.
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PMID:Heterogeneity in the radiosensitizing effects of the DNA ligand hoechst-33342 in human tumor cell lines. 1799 47


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