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)

A range of pure, monomeric porphyrins were synthesised and their localising capacities compared to HpD and Hp at 6 h and 24 h post injection in the mouse C6 intracerebral glioma model as well as in normal brain, skin, muscle, kidney, spleen, liver, lung and whole blood. The partition coefficients were examined between PBS and 2-octanol over the pH range 7.4-6.6 and pH profiles were established. A parabolic relationship was observed between log (porphyrin tumour concentration) at pH 7.4, with maximal tumour localisation at log (partition coefficient), pi, of approximately zero. Porphyrins with side chains with nett cationic character also exhibited up upward (parabolic) dependence on pi for most tissues studied, with maximal porphyrin localisation at pi of 0-0.5. In contrast, those porphyrins with nett anionic character exhibited a downward (negative) parabolic trend for all eight tissues studied, with minimal porphyrin localisation at pi of approximately zero. Four porphyrins (4, 11, 12, 13) exhibited similar or better tumour localisation than HpD, and two (11 and 12) offer promise as lead compounds for the design of improved porphyrins for use in PDT.
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PMID:Evaluation of tumour and tissue distribution of porphyrins for use in photodynamic therapy. 155 83

The distribution of diazepam binding inhibitor (DBI), a multi-function peptide which has recently been discovered, was studied in the rat and human central nervous system and in peripheral organs of the rat by light and electron microscopical immunohistochemistry. In the central nervous system, DBI-LI was localized in many glial cells and glial tumors, and in some neurons. In the periphery, DBI-LI was found in many tissues but it was expressed selectively in specialized cell types. Intense DBI-LI was observed in some endocrine, steroid-producing cells such as glomerular cells of the adrenal gland and Leydig cells of the of the testis. Different types of epithelial cells, for instance distal convoluted tabular cells of the kidney and mucosal cells of the small intestine, displayed moderate DBI-LI. Some supporting cells, such as Schwann cells and Sertoli cells, were also immunopositive. The frequent localization of DBI in cells, also known to contain large amounts of mitochondrial benzodiazepine receptors, indicates that DBI may play an important role as an endogenous regulator of intracellular metabolic functions via the mitochondrial benzodiazepine receptor.
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PMID:Immunohistochemistry of diazepam binding inhibitor (DBI) in the central nervous system and peripheral organs: its possible role as an endogenous regulator of different types of benzodiazepine receptors. 166 66

We have shown that several human malignant glioma cell lines are stimulated by bacterial lipopolysaccharide (E. coli 0111:B4, 1 microgram/ml) to produce a high molecular weight (> 200 kD) growth activity for BALB 3T3, clone A31 cells. This glioma-derived growth factor (GDGF-2) acts like a 'competence' factor. Malignant glioma cell line D-54 MG constitutively produced GDGF-2, which we have partially characterized from serum-free conditioned culture medium. GDGF-2 is resistant to heat (100 degrees C, 5 min), acidic (pH 2, 2 hr) or reducing (0.5 M 2 ME, 30 min) conditions as well as exposure to RNases; however, it is sensitive to > 4 freeze-thaw cycles, alkaline (pH 11, 2 hr) conditions or pre-treatment with proteolytic enzymes. GDGF-2 had a pl of 6.8 determined by preparative isoelectric focusing, bound to DEAE, with elution at 35 and 185 mM NaCl and at 43% acetonitrile from a C4 reversed phase column. GDGF-2 activity was not neutralized by antibodies to TGF alpha, TGF beta, PDGF, VEGF or TNF alpha indicating that it is not immunochemically related to these growth factors. However GDGF-2 co-chromatographed on Superose 12 HPLC (250 x 9 mm; 5% isopropanol, 6 mM CHAPS in PBS) with a substance that suppressed growth of mink lung epithelial cells (Mv1Lu), but not BALB 3T3 cells, and could be neutralized by anti-TGF beta antibodies. GDGF-2 activity eluted from heparin columns in 0.6 M NaCl; thus, it is not a heparin binding growth factor. D-54 MG cell line produced alpha 2-macroglobulin (alpha 2M), which is known to bind TGF beta; however, immunoprecipitation of alpha 2M did not deplete TGF beta or GDGF-2 activity. Further, neither GDGF-2 or TGF beta can be dissociated into lower molecular weight active components by chromatography in high salt (2 M NaCl) or 2-ME (0.5 M). GDGF-2 may be a novel autocrine or paracrine mitogen, stimulating mitotic division or interfering with normal cell growth regulation.
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PMID:Partial characterization of glioma-derived growth factor 2: a novel mitogenic activity from human cell line D-54 MG. 814 64

The mitochondrial DBI receptor complex (mDRC; previously called the peripheral benzodiazepine receptors) is linked to the production of neurosteroids such as pregnenolone sulfate, dehydroepiandrosterone sulfate, and others. In order to gain further information as to the function of the mDRC in the brain, we have constructed and tested both in vitro and in vivo a novel series of ligands, 2-arylindole-3-acetamides. The SAR studies detailed herein delineate some of the structural features required for high affinity binding to the mDRCs. In most cases the new ligands were prepared by use of the Fischer indole synthesis. Variations in the length and number of the alkyl groups on the amide nitrogen were probed together with the effects of halogen substituents on one or both of the aryl rings. Some ligands were also synthesized for study which represent conformationally constrained versions of the parent structure. Broad screening studies revealed these indoleacetamides to be highly selective for the mDRC, since they failed to bind with any significant affinity to other receptor systems. Some of the ligands were found to exhibit Ki values in the low nanomolar range for the mDRC as measured by the displacement of [3H]4'-chlorodiazepam. A subset of these ligands was also shown to stimulate pregnenolone formation from the mitochondria of C6-2B glioma cells with an EC50 of about 3 nM. In animal experiments ligands selected for further study were found to exhibit antineophobic effects, in spite of the fact that they exhibit no direct action on GABAA receptors. Consequently, it is postulated that these ligands owe their action to an indirect modulation of GABAA receptor function, presumably by stimulation of neurosteroid production and release from glial cells, followed by neurosteroid modulation of GABA's action on the chloride ion channel conductance of GABAA receptors.
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PMID:Chemistry, binding affinities, and behavioral properties of a new class of "antineophobic" mitochondrial DBI receptor complex (mDRC) ligands. 841 Oct 7

Malignant gliomas remain refractory to intensive radiotherapy and cellular hypoxia enhances clinical radioresistance. Under hypoxic conditions, the benzotriazine di-N-oxide (3-amino-1,2,4-benzotriazine 1,4-dioxide) (tirapazamine) is reduced to yield a free-radical intermediate that results in DNA damage and cellular death. For extracranial xenografts, tirapazamine treatments have shown promise. We therefore incorporated tirapazamine into the synthetic, biodegradable polymer, measured the release, and tested the efficacy both alone and in combination with external beam radiotherapy in the treatment of experimental intracranial human malignant glioma xenografts. The [(poly(bis(p-carboxyphenoxy)-propane) (PCPP):sebacic acid (SA) (PCPP:SA ratio 20:80)] polymer was synthesized. The PCPP:SA polymer and solid tirapazamine were combined to yield proportions of 20% or 30% (wt/wt). Polymer discs (3 x 2 mm) (10 mg) were incubated (PBS, 37 degrees C), and the proportion of the drug released vs. time was recorded. Male nu/nu nude mice were anesthetized and received intracranial injections of 2 x 10(5) U251 human malignant glioma cells. For single intraperitoneal (i.p.) drug and/or external radiation treatments, groups of mice had i.p. 0.3 mmol/kg tirapazamine, 5 Gy cranial irradiation, or combined treatments on day 8 after inoculation. For fractionated drug and radiation treatments, mice had i.p. 0.15 mmol/kg tirapazamine, 5 Gy radiation, or combined treatments on days 8 and 9 after inoculation. For intracranial (i.c.) polymer treatments, mice had craniectomies and intracranial placement of polymer discs at the site of cellular inoculation. The maximally tolerated percentage loading of tirapazamine in the polymer.disc was determined. On day 7 after inoculation, groups of mice had i.c. empty or 3% tirapazamine alone or combined with radiation (5 Gy x 2 doses) or combined with i.p. drug (0.15 mmol/kg x 2 doses on days 8 and 9). Survival was recorded. Polymers showed controlled, protracted in vitro release for over 100 days. The 5 Gy x 1 treatment resulted in improved survival; 28.5 +/- 3.7 days (P = 0.01 vs. controls), while the single i.p. 0.3 mmol/kg tirapazamine treatment, 17.5 +/- 1.9 days (P = NS) and combined treatments; 21.5 +/- 5.0 days (P = NS) were not different. The fractionated treatments: 5 Gy x 2, i.p. 0.15 mmol/kg tirapazamine x 2 and the combined treatments resulted in improved survival: 44.5 +/- 3.9 (P < 0.001), 24.5 +/- 2.3 (P = 0.05) and 50.0 +/- 6.0 (P < 0.001), respectively. Survival after intracranial empty polymer was 16.5 +/- 3.0 days and increased to 31.0 +/- 3.0 (P = 0.003) days when combined with the 5 Gy x 2 treatment. The survival after the polymer bearing 3% tirapazamine alone vs. combined with radiation was not different. The combined 3% tirapazamine polymer, i.p. tirapazamine, and radiation treatments resulted in both early deaths and the highest long-term survivorship. The basis for potential toxicity is discussed. We conclude that implantable biodegradable polymers provide controlled intracranial release for treatment of experimental glioma. For treatment of malignant gliomas, the combination of continuous polymer-mediated delivery and fractionated systemic delivery of tirapazamine with external beam radiotherapy warrants further exploration.
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PMID:Implantable polymers for tirapazamine treatments of experimental intracranial malignant glioma. 1049 62

The ability of certain viruses to lyse cancer cells suggests that they may have potential as oncolytic agents. We investigated the effect of vaccinia virus (VV) and its recombinant derivatives (recVV2, rVV-p53) on growth of C6 rat glioma cells that form fast growing tumors in athymic nude mice. VV effectively infected C6 cells in vitro, inducing high level of foreign gene expression. Most of C6 cells infected in vitro with rVV-p53 expressing the tumor suppressor p53 protein showed apoptosis specific morphological changes in DAPI-stained nuclei and DNA fragmentation pattern on gel electrophoresis; infection with VV induced low level of cell apoptosis. In an ex vivo experiment, VV-infected C6 cells were implanted s.c. in athymic nude mice and tumor development was monitored. In contrast to the control PBS group, most of mice implanted with infected cells remained tumor free until the end of the observation period. In an in vivo experiment, injection of VV or rVV-p53 after the C6 cells had been implanted in nude mice induced effective inhibition of tumor growth in comparison with control PBS groups. The oncolytic effect was greater with rVV-p53, apparently due to overexpressed p53 and p53-mediated cell apoptosis. In study of virus virulence we did not observe disease symptoms in athymic mice infected with a high dose of VV. Experimental results indicate that vaccinia virus itself and vaccinia-mediated delivery of therapeutic genes represent novel potential strategies for tumor therapy.
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PMID:Antitumor effect of vaccinia virus in glioma model. 1052 73

To evaluate the efficacy and toxicity of dendritic cell (DC) based therapy for intracerebral gliomas, we utilized a cell line derived from an astrocytoma that arose spontaneously in a VM/Dk mouse. This astrocytoma mirrors human gliomas phenotypically, morphologically and secretes transforming growth factor (TGF)-betas, immunosuppressive cytokines secreted by human gliomas. Systemic vaccination of mice with DCs pulsed with tumor homogenate followed by intracranial tumor challenge produced a > 160% increase in median survival (p = 0.016) compared with mice vaccinated with PBS or unpulsed DCs (p = 0.083). Fifty percent of mice treated with pulsed DCs survived long-term. Immunologic memory was demonstrated by survival of mice rechallenged with tumor. Both cell-mediated and humoral immunity was induced. On histological examination only focal areas of demyelination at the tumor implantation site were present. There was no evidence that autoimmune encephalomyelitis was induced by DC vaccination. Therefore, in a murine model, vaccination with DCs pulsed with glioma tumor homogenate is a safe and effective therapy against a syngeneic glioma located in the immunologically privileged central nervous system (CNS).
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PMID:Bone marrow-derived dendritic cells pulsed with tumor homogenate induce immunity against syngeneic intracerebral glioma. 1067 85

We evaluated the interaction between oncolytic, replication-competent adenoviral vectors and the herpes simplex virus-1 thymidine kinase (HSV1-tk) gene/ganciclovir (GCV) suicide system for the treatment of malignant gliomas. We constructed a panel of replication-competent adenoviral vectors in which the luciferase (IG.Ad5E1(+). E3Luc) or HSV1-tk gene (IG.Ad5E1(+).E3TK) replace the M(r) 19,000 glycoprotein (gp19K) coding sequence in the E3 region. IG.Ad5E1. IG.Ad5.ClipLuc and IG.AdApt.TK are E1-deleted viruses that contain the luciferase or the HSV1-tk gene in the former E1 region driven by the human cytomegalovirus promoter. IG.Ad5. Sarcoma 1800HSA.E3Luc contains an irrelevant gene in the E1 region, whereas the gp19K coding sequence in the E3 region is replaced by the luciferase gene as in the replicating virus IG.Ad5E1(+).E3Luc. For in vitro experiments, we used a panel of human glioma cell lines (U87 MG, T98G, A172, LW5, and U251), a rat gliosarcoma cell line (9 L), and human lung (A549) and prostate carcinoma (P3) cell lines. In vitro, GCV sensitivity (10 microg/ml) was studied in U87 MG cells after infection at a multiplicity of infection of 1 and 10. A s.c. U87 MG glioma xenograft model was established in NIH-bg-nu-xid mice. Tumors of 100-150 mm(3) were treated with a single injection of adenovirus 10(9) IU suspended in 100 microl of PBS, and GCV 100 mg/kg was administered i.p. twice daily for 7 days. The cytopathic effect of all three replication-competent adenoviral vectors was similar to the cytopathic effect of wild-type adenovirus 5 on all human cell lines tested, indicating that deletion of the E3 gp19K sequences did not affect the oncolytic effect of the vectors. In vitro, luciferase expression was the same for both E1-deleted vectors (IG.Ad5.ClipLuc and IG.Ad5. Sarcoma 1800HSA.E3Luc), demonstrating the strength of the internal E3 promoter even in the absence of E1A. However, in vitro expression levels obtained with replication-competent IG.Ad5E1(+). E3Luc were 3 log higher (allowing infection with a 2-3-log lower multiplicity of infection) in the human cell lines. In U87 MG glioma cells, the oncolytic effect of replication-competent IG.Ad5E1(+).E3TK was significantly enhanced by the addition of GCV and greatly exceeded the cytotoxicity of replication-incompetent IG.AdApt.TK combined with GCV. In established s.c. U87 MG glioma xenografts, a single injection of IG.Ad5E1(+).E3TK resulted in a significant slowing of tumor growth and prolonged survival compared with injection of IG.AdApt.TK. Addition of GCV slowed tumor growth, further adding to survival. In conclusion, the oncolytic effect of replicating adenoviral vectors and HSV1-tk/GCV have potent antitumor effects in gliomas. When combined, these two approaches are complementary, resulting in a significantly improved treatment outcome. In addition, replication-competent adenoviral vectors missing the E3 gp19K coding sequences, have oncolytic efficacy comparable with wild type. In combination with high expression levels obtained with the natural E3 promoter, such vectors are promising new anticancer agents.
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PMID:Treatment of malignant gliomas with a replicating adenoviral vector expressing herpes simplex virus-thymidine kinase. 1175 94

Heat shock proteins are recognized as significant participants in immune reactions. In this study, we have demonstrated that the cell surface presentation of MHC class I antigen was increased in tandem with increased heat shock protein 70 (HSP70) expression and the immunogenicity of rat T-9 glioma cells was enhanced by hyperthermia. T-9 cells showed growth inhibition for 24 h after the heat treatment at 43 degrees C for 1 h in vitro, but then resumed a normal growth rate. HSP70 expression reached a maximum at 24 h after heating. Flow cytometric analysis revealed a significant increase in MHC class I antigen on the surface of the heated cells. The augmentation of MHC class I surface expression started 24 h after heating and reached a maximum 48 h after heating. The expression of other immunologic mediators, such as intracellular adhesion molecule-1 (ICAM-1) and MHC class II antigens, did not increase. In an in vivo experiment using immunocompetent syngeneic rats (F344), growth of the heated T-9 cells, with augmentation of MHC class I antigen surface expression, was significantly inhibited, while the cells grew progressively in nude rats (F344/N Jcl-rnu). Furthermore, compared with lymphocytes from non-immunized (PBS only injection) rats or rats injected with non-heated T-9 cells, the splenic lymphocytes of the rats in which the heated T-9 cells were injected displayed specific cytotoxicity against T-9 cells. These results suggest that HSP70 is an important modulator of tumor cell immunogenicity, and that hyperthermic treatment of tumor cells can induce the host antitumor immunity via the expression of HSP70. These results may benefit further efforts on developing novel cancer immunotherapies based on hyperthermia.
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PMID:Augmentation of MHC class I antigen presentation via heat shock protein expression by hyperthermia. 1177 73

The loss of gap junctional intercellular communication has been proposedas playing a major role in the process of carcinogenesis. Most neoplastic cells, including C6 gliomas, express less connexins and have fewer gap junctions, reduced gap junctional intercellular communication, and increased growth rates compared with their nonneoplastic counterparts. The purpose of this study was to determine whether ciliary neurotrophic factor (CNTF) can be used to increase endogenous connexin43 levels, increase intercellular coupling, and retard the growth rate of C6 glioma cells. C6 cells were grown in serum-reduced medium (1% serum) and exposed to the following agents: vehicle (PBS), CNTF (20 ng/ml), CNTF soluble receptor (CNTFRalpha; 200 ng/ml), or Complex (CNTF + CNTFRalpha). Reverse transcription-PCR analysis indicated that C6 cells express CNTF mRNA but not CNTFRalpha mRNA. When cells were exposed to the above agents, only Complex caused an up-regulation of connexin43 protein (based on immunocytochemical and immunoblot analysis). Furthermore, Complex increased gap junctional coupling in C6 cells as noted by the passage of the gap junction permeable dye calcein. Finally, it was demonstrated that Complex-treatment reduces the growth rate of C6 cells compared with all of the other agents tested. Taken together, this study has demonstrated that CNTF in combination with its soluble receptor can increase connexin43 expression, increase gap junctional coupling, and reduce the in vitro proliferation of C6 glioma cells.
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PMID:Ciliary neurotrophic factor (CNTF) in combination with its soluble receptor (CNTFRalpha) increases connexin43 expression and suppresses growth of C6 glioma cells. 1206 2


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