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)

Oxygen radicals induce cytotoxicity via a variety of mechanisms, including DNA damage, lipid peroxidation and protein oxidation. Here, we explore the use of a polyethylene glycol (PEG)-stabilised enzyme capable of producing reactive oxygen species (ROS), glucose oxidase (GO), for the purpose of harnessing the cytotoxic potential of ROS for treating solid tumours. PEG-GO (200 U), administered by two intratumoral injections 3 h apart, produced a significant growth delay in subcutaneous rat 9L gliomas as compared with control animals receiving heat-denatured PEG-GO. Rats were protected from systemic toxicity by subsequent i.v. administration of PEG-superoxide dismutase (PEG-SOD) and PEG-catalase. In vivo tumour metabolic changes, monitored using 31P magnetic resonance spectroscopy (31P-MRS) 6 h following initial administration of PEG-GO, revealed a 96 +/- 2% reduction in the ATP/Pi ratio and a 0.72 +/- 0.10 unit decline in intracellular pH. A 3-fold sensitisation of 9L glioma cells in vitro to hydrogen peroxide could be achieved by a 24 h preincubation with buthionine sulphoximine (BSO). This study suggests that oxidation therapy, the use of an intratumoral ROS-generating enzyme system for the treatment of solid tumours, is a promising area which warrants further exploration.
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PMID:Oxidation therapy: the use of a reactive oxygen species-generating enzyme system for tumour treatment. 798 Oct 65

Oligodendroglia-glioma hybrid cells (ROC-1) subjected to inhibition of glycolytic and oxidative ATP synthesis undergo a sequence of changes, including ATP depletion, parallel processes of cell swelling and blebbing, and finally plasma membrane disruption and cell death. The morphological and biochemical changes that follow ATP depletion were studied in the presence and absence of polyethylene glycol (M(r) 8,000), a nonpermeant oncotic agent. Polyethylene glycol prevented cell swelling and membrane blebbing. It significantly delayed, but did not prevent, the release of lactate dehydrogenase into the medium; it did not affect the fall in [ATP]. These results suggest that osmotic cell swelling may be a contributing factor in the loss of cell viability when ROC-1 cells are depleted of ATP.
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PMID:Protection of ROC-1 hybrid glial cells by polyethylene glycol following ATP depletion. 837 11

In C6-2B rat glioma cells, agonist-stimulated cAMP accumulation is potently inhibited after the stimulation of endogenous bradykinin receptors or stably transfected substance K receptors, coupled to phosphatidylinositol hydrolysis. In the present report, pharmacological tools were used to selectively stimulate either protein kinase C or Ca2+, the two final effectors activated upon phosphatidylinositol hydrolysis, and their role in the inhibition of the C6-2B cell cAMP signaling pathway was investigated. Activation of protein kinase C by an acute treatment with phorbol 12-myristate 13-acetate or L-alpha-1-oleoyl-2-acetyl-sn-3-glycerol did not reduce, but rather enhanced, the cAMP accumulation elicited by forskolin, a direct activator of adenylyl cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1]. This effect was antagonized by the protein kinase inhibitor H-7 and mimicked by the protein phosphatase inhibitor okadaic acid. Thapsigargin, a selective microsomal Ca(2+)-ATPase inhibitor, evoked a sustained increase in the intracellular free Ca2+ concentration, with an EC50 of 24.8 +/- 4.3 nM, and inhibited the cAMP accumulation induced by the beta-adrenergic receptor agonist isoproterenol with comparable potency (IC50 = 19.3 +/- 0.2 nM), strongly suggesting a causal relationship between the two phenomena. The inhibition by thapsigargin of isoproterenol- or forskolin-stimulated cAMP accumulation was not affected by pertussis toxin or down-regulation or inhibition of protein kinase C. Dantrolene, a blocker of Ca2+ release from intracellular stores, antagonized 1) the Ca2+ transient in response to thapsigargin and substance K and 2) the inhibitory effect of these compounds on isoproterenol- or forskolin-induced cAMP accumulation. Moreover, sequestration of intracellular Ca2+ with the cell-permeable Ca2+ chelator ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid acetoxymethyl ester abolished the cAMP inhibition mediated by thapsigargin. Finally, isoproterenol- or forskolin-stimulated adenylyl cyclase activity in digitonin-permeabilized cells was not affected by either thapsigargin or substance K. These data provide compelling evidence that increases in intracellular free Ca2+ concentration without activation of protein kinase C suffice and are responsible for the inhibition of cAMP accumulation in C6-2B cells.
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PMID:Ca2+ inhibition of beta-adrenergic receptor- and forskolin-stimulated cAMP accumulation in C6-2B rat glioma cells is independent of protein kinase C. 838 3

Cadmium ions did not influence the binding of endothelin-1 (ET-1) to its receptor on the surface of rat glioma C6 and rat aorta A10 cells. This was studied (a) by the binding of 1251-ET-1 to intact cells in the absence or presence of cadmium (Cd2+) and (b) by analysis of the receptor/ET-1 complex after crosslinking with disuccinimidyl suberate (DSS) or ethylene glycol-bis-(succinimidyl succinate) (EGS) on SDS PAGE. Using Fura-2 and Quin-2 loaded C6 rat glioma cells, it was shown that Cd2+ ions strongly interfered with the ET-1 induced Ca(2+)-influx in C6 glioma cells (IC50 approximately 10 microM).
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PMID:Influence of cadmium ions on endothelin-1 binding and calcium signaling in rat glioma C6 cells. 855 74

The effect of systemic injection of modified hemoglobin (Hb) prepared from bovine, human, or mouse Hb on tumor oxygenation was investigated. Hb was modified by (1) diisothiocyanatobenzenesulfonate (DIBS) to yield cross-linking within a tetramer; (2) glycolaldehyde (Glyal) to yield cross-linking between and within tetramers; (3) carboxymethylation (Cm) to change oxygen affinity; or (4) poly(ethylene glycol) (PEG) to yield attachment between tetramers. HGL9 (human glioma) in nude mice and FSaII (mice fibrosarcoma) in C3H mice were used as tumor models. Dose and time dependency were detected in the oxygenation effect by bovine-PEG-Hb. Internal cross-linkage prolonged the half-life in the circulation, and thus showed a significant effect. Compared to bovine-CmHb, bovine-DIBS-Hb and bovine-DIBS-CmHb were more effective. Decreasing the oxygen affinity by Cm significantly enhanced tumor oxygenation. Human-DIBS-CmHb was more effective than human-DIBS-Hb. These effects were caused by oxygen carrying capacity of modified Hbs as well as hemodynamic factors, and the injection seemed to reduce both perfusion-limited (acute) and diffusion-limited (chronic) hypoxia.
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PMID:Oxygenation in tumors by modified hemoglobins. 864 36

We developed a novel magnetic resonance (MR) imaging contrast agent, MAb-magnetite, that was prepared by covalently linking polyethylene glycol-coated magnetite to a monoclonal antibody specific for a human glioma cell-surface antigen. When MAb-magnetite was injected intravenously into tumor-bearing nude mice at a dose of 100 mumol Fe/kg body weight, a 50% decrease in the T2 signal intensity of the tumor was observed, immediately following administration and continued for 48 h. Microscopic observation of the tumor tissue demonstrated localization of MAb-magnetite in cancer cells. These results suggest that MAb-magnetite is a promising agent for MR imaging of neoplasms.
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PMID:Development of a target-directed magnetic resonance contrast agent using monoclonal antibody-conjugated magnetic particles. 895 18

Pharmacokinetics and tissue distribution of daunomycin and different liposomal formulations of daunomycin were determined. Special emphasis was thereby given to immunoliposome-mediated drug delivery. Three different types of 85 nm liposomes were used for this study: 1) conventional liposomes, 2) liposomes sterically stabilized with 2000 Dalton polyethylene glycol and 3) immunoliposomes prepared by coupling a control IgG2a or monoclonal antibody to the distal end of the polyethylene glycol spacer. The antibody used was the OX26 monoclonal antibody to the rat transferrin receptor. Daunomycin and liposomes were administered by i.v. injection to the rat. Daunomycin and daunomycin in conventional liposomes were rapidly cleared from the plasma compartment. When compared to the free drug, daunomycin in conventional liposomes did accumulate to higher levels in liver and spleen and to lower levels in heart, lung and liver. In contrast, daunomycin in liposomes sterically stabilized with polyethylene glycol could not be detected in heart, lung, kidney, liver and spleen. Using nonspecific IgG2a isotype immunoliposomes, tissue concentrations of immunoliposomes were reduced by at least a factor of two. Attachment of more than 29 OX26 monoclonal antibodies per liposome did not increase tissue levels in heart, kidney or lung. Tissue levels of OX26 immunoliposomes were reduced in all organs by coinjection of unbound OX26. In vitro, endocytosis of fluorescent immunoliposomes by RG2 rat glioma cells was observed. These data indicate that receptor mediated drug delivery to different tissues can be achieved using OX26 conjugated immunoliposomes.
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PMID:Receptor mediated delivery of daunomycin using immunoliposomes: pharmacokinetics and tissue distribution in the rat. 931 70

Human brain gliomas overexpress the receptor for epidermal growth factor (EGF), and radiolabeled EGF is a potential peptide radiopharmaceutical for imaging human brain tumors, should this peptide be made transportable through the blood-brain barrier (BBB) in vivo. Peptide drug delivery to the brain may be facilitated by conjugating peptide radiopharmaceuticals to BBB drug delivery vectors such as the OX26 monoclonal antibody (MAb), which undergoes receptor-mediated transcytosis through the BBB via the brain capillary endothelial transferrin receptor. EGF was biotinylated with NHS-XX-biotin, where NHS = N-hydroxysuccinimide and -XX- = bis (aminohexanoyl) spacer arm. The [125I]EGF-XX-biotin rapidly bound to C6 rat glioma cells transfected with the human EGF receptor. However, no binding to the C6 EGF receptor was detected when the [125I]EGF-XX-biotin was bound to a conjugate of streptavidin (SA) and the OX26 MAb. An alternative linker strategy using poly(ethylene glycol) (PEG) of 3400 Da molecular mass (PEG3400) was evaluated, wherein EGF was monobiotinylated with NHS-PEG3400-biotin. Attachment of the [125I]EGF-PEG3400-biotin to the OX26/SA conjugate did not impair binding of the construct to the EGF receptor in C6 glioma cells. The length of the -PEG- spacer arm and the -XX- spacer arm was >200 atoms and 14 atoms, respectively. These studies demonstrate that the use of the extended PEG linker releases steric hindrance of MAb transport vectors on binding of EGF to its cognate receptor on glioma cells. Attachment of EGF peptide radiopharmaceuticals to BBB drug delivery systems such as the OX26 MAb using extended PEG linkers allows for retention of the bifunctionality of the conjugate with binding to both EGF and transferrin receptors.
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PMID:Retention of biologic activity of human epidermal growth factor following conjugation to a blood-brain barrier drug delivery vector via an extended poly(ethylene glycol) linker. 989 61

Epidermal growth factor (EGF) is a potential peptide radiopharmaceutical for detection of brain tumors, because many human gliomas overexpress the EGF receptor (EGFR). The transport of EGF to the brain, however, is restricted by the blood-brain barrier (BBB). The purpose of the present study was to develop a vector-mediated brain delivery system for radiolabeled EGF. Human EGF was monobiotinylated with NHS-PEG3400-biotin, where NHS is N-hydroxysuccinimide and PEG3400 is poly(ethylene glycol) of 3400 Da molecular mass. EGF-PEG3400-biotin was radiolabeled with either 125I or 111In through the metal chelator, diethylenetriaminepentaacetic acid (DTPA). The radiolabeled EGF was then conjugated to a BBB delivery vector comprised of a complex of the OX26 monoclonal antibody (MAb) to the rat transferrin receptor, which was coupled to streptavidin (SA). Following intravenous injection in rats, the 125I conjugate was rapidly degraded in vivo, while the 111In conjugate was metabolically stable. The brain delivery of [111In]DTPA-EGF-PEG3400-biotin was enabled by conjugation with OX26/SA and was optimized by co-injection of unlabeled EGF to saturate EGF receptors in the liver. The specific binding of the [111In]DTPA-EGF-PEG3400-biotin conjugated to OX26/SA to the EGF receptor was confirmed in C6 rat glioma cells, which had been transfected with a gene encoding for the human EGF receptor under the regulation of a dexamethasone-inducible promoter. In vivo studies of C6-EGFR experimental tumors in Fischer 344 rats demonstrated successful brain imaging only when the peptide radiopharmaceutical was conjugated to the BBB delivery system, although the C6-EGFR tumors did not express EGFR in vivo. In conclusion, these studies describe the molecular formulation of a peptide radiopharmaceutical that can be used for imaging brain tumors behind the BBB.
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PMID:Epidermal growth factor radiopharmaceuticals: 111In chelation, conjugation to a blood-brain barrier delivery vector via a biotin-polyethylene linker, pharmacokinetics, and in vivo imaging of experimental brain tumors. 1034 84

The goal of this investigation was to measure changes in vascular permeability, pore cutoff size, and number of transvascular transport pathways as a function of time and in response to vascular endothelial growth factor (VEGF), placenta growth factor (PIGF-1 and PIGF-2), or basic fibroblast growth factor (bFGF). Two human and two murine tumors were implanted in the dorsal skin chamber or cranial window. Vascular permeability to BSA (approximately 7 nm in diameter) and extravasation of polyethylene glycol-stabilized long-circulating liposomes (100-400 nm) and latex microspheres (approximately 800 nm) were determined by intravital microscopy. Vascular permeability was found to be temporally heterogeneous. VEGF superfusion (100 ng/ml) significantly increased vascular permeability to albumin in normal s.c. vessels, whereas a 30-fold higher dose of VEGF (3000 ng/ml) was required to increase permeability in pial vessels, suggesting that different tissues exhibit different dose thresholds for VEGF activity. Furthermore, VEGF superfusion (1000 ng/ml) increased vascular permeability to albumin in a hypopermeable human glioma xenograft in cranial window, whereas VEGF superfusion (10-1000 ng/ml) failed to increase permeability in a variety of hyperpermeable tumors grown in dorsal skin chamber. Interestingly, low-dose VEGF treatment (10 ng/ml) doubled the maximum pore size (from 400 to 800 nm) and significantly increased the frequency of large (400 nm) pores in human colon carcinoma xenografts. PIGF-1, PIGF-2, or bFGF did not show any significant effect on permeability or pore size in tumors. These findings suggest that exogenous VEGF may be useful for augmenting the transvascular delivery of larger antineoplastic agents such as gene targeting vectors and encapsulated drug carriers (typical range, 100-300 nm) into tumors.
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PMID:Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor. 1046 18


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