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)

To investigate the value of direct measurement of the rate constants by performing 18F-labeled fluorodeoxyglucose (FDG) studies of glucose consumption in human gliomas in vivo, a kinetic method with 3- and 4-parameter rate constant models for FDG uptake was used to analyze data from dynamic scans obtained by positron emission tomography after injection of FDG into 14 patients with glioma. The results were compared with those obtained by the autoradiographic method using 3- and 4-parameter rate constant models. There were no significant differences in the glucose consumption calculated by the four different methods both in the gliomas and in the contralateral intact cortex. It was found that the rate constant k4* could be neglected in calculation of glucose consumption in gliomas as well as in the contralateral intact cortex. The rate constant k3*, an index of hexokinase function, was higher in malignant gliomas than in benign gliomas and was close to that in the contralateral cortex. This study indicates that the 3-parameter autoradiographic method, which is the most common one used in clinical practice, is reliable for the calculation of glucose consumption in human gliomas. Furthermore, direct measurement of the regional rate constants for FDG by the kinetic method was found to be useful for evaluation of the biochemical and physiological characteristics of human gliomas in vivo.
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PMID:Glucose consumption and rate constants for 18F-fluorodeoxyglucose in human gliomas. 170 Mar 16

Three cell lines established from human gliomas were found to differ in the capacity to phosphorylate the glycolytic enzyme pyruvate kinase in vitro. Phosphorylation in the glioblastoma cell line U-138 was more pronounced than in the glioma cell line Hs 683 and in the glioblastoma cell line A-172. All 3 cell lines showed similar pyruvate kinase isozyme patterns and expressed about 90% K-type and 10% M-type subunits. So, differences in pyruvate kinase phosphorylation could not be explained by differences in the availability of the appropriate substrate, being pyruvate kinase type K. As in gliomas, phosphorylation could specifically and almost completely be inhibited by fructose-1,6-bisphosphate. In order to investigate a potential physiological significance of the phosphorylation of pyruvate kinase, we have characterized these cell lines for several glycolytic parameters. In U-138 cells, the production of lactate appeared to be 2 times higher as compared with A-172 and Hs 683 cells under normal growth conditions and even 4 times higher under low glucose culture regime. The efflux of lactate correlated with the pyruvate kinase phosphorylation pattern in the cell lines. In none of the cell lines could the lactate production be stimulated by glutamine as additional energy source under low glucose culture conditions. The higher glycolytic flux in U-138 cells was not accompanied by higher glycolytic enzyme activities. The isozyme patterns of hexokinase, pyruvate kinase, aldolase, enolase and lactate dehydrogenase in the cell lines were nearly identical and resembled the patterns previously described for solid gliomas. However, the isozyme composition of phosphofructokinase in the cell lines differed from the situation in gliomas. While in gliomas the expression of L-type phosphofructokinase is favored, in the glioma cell lines, we found an increase in the expression of C-type subunits.
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PMID:Phosphorylation of pyruvate kinase and glycolytic metabolism in three human glioma cell lines. 179 9

Among new therapeutic modalities for both primary and secondary brain tumors, selective manipulation of metabolic pathways seems attractive. In human malignant gliomas and cell lines from a glioblastoma multiform, lonidamine has been shown to interfere with aerobic glycolysis with a decrease of lactate production by the inhibition of a mitochondrially-bound hexokinase; this selective reduction of the energetic capabilities of glioma cells would be a limiting factor for processes requiring energy, such as cell growth and recovery from potentially lethal damage after radiotherapy or chemotherapy. The activity of lonidamine in malignant gliomas after surgery in association with conventional radiotherapy is being investigated, while previous studies have suggested a limited, but clear therapeutic activity of the drug in recurrent malignant gliomas. In brain metastases lonidamine has not been effective as a radiation enhancer, but has been shown to potentiate systemic chemotherapy. Most common side effects were myalgias, testicular pain and ototoxicity with no serious organ toxicity or myelosuppression.
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PMID:Lonidamine in malignant brain tumors. 203 Nov 97

Comparisons of glycolytic enzymes between rapidly proliferating and Bt2 cAMP-induced differentiated C6 glioma cells have been made. Rapidly proliferating cells had higher concentrations of glucose-6-phosphate, fructose-6-phosphate and fructose-1,6-bisphosphate compared to morphologically differentiated cells. Under maximally activating conditions, the specific activity and Vmax of hexokinase and phosphofructokinase enzymes were reduced by approximately 3- and 28-fold, respectively, in differentiated cells, without any change in Km values. These results suggest that hexokinase and phosphofructokinase occupy special control positions and the rate of glycolysis is correlated with cellular proliferation of C6 glioma cells.
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PMID:Activities of glycolytic enzymes in rapidly proliferating and differentiated C6 glioma cells. 252 90

Up-to-date unsatisfactory results obtained in multimodality treatments of malignant glioma have prompted the research of new therapeutic modalities with 'unconventional' modes of action. Lonidamine (LND) is a drug which reduces aerobic glycolytic activity in both human and experimental tumors. This effect mainly depends on the inhibition of mitochondrially-bound hexokinase (HK) which is present in large amounts in malignant cells. A Phase II study was conducted on patients with recurrent glioma; 12 patients were admitted to the study. Clinical side effects were moderate, necessitating a reduction of the dosage in only 1 case. The objective results were evaluated according to the indications of Levin. 2 responders and 3 cases of stable disease were observed out of 10 evaluable patients. The potential value of this new drug is discussed.
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PMID:The potential role of lonidamine (LND) in the treatment of malignant glioma. Phase II study. 266 93

Among the features of the reprogrammed neoplastic phenotype there is the metabolic property to display an increased glycolytic capacity and the ability to convert glucose to lactic acid in the presence of oxygen. Human gliomas in vivo and in vitro are capable to metabolize glucose in a way strictly related to the pathological degree of malignancy. The drug Lonidamine [1-(2,4-dichlorobenzyl)-1H-indazol-3 carboxylic acid)] (LND) is able to selectively block hexokinase (HK) activity and, consequently, lactate production only in highly glycolytic (highly malignant) gliomas, stimulating, on the contrary, that of low grade gliomas; this basically depends on the different HK patterns between low and high grade gliomas. LND is under clinical trial in order to evaluate its effectiveness in glioma therapy.
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PMID:Modulation of glycolysis in neuroepithelial tumors. 267 59

Mitochondrially bound hexokinase (ATP-D-hexose-6-phosphotransferase; EC 2.7.1.1) was dissociatively extracted from normal rat brains and intracerebral and subcutaneous implants of the 36B-10 glioma. At least 70% of the total hexokinase enzyme activity in normal and glioma tissue was associated with the mitochondrial fraction. Purification of the crude tissue extracts by ion-exchange and affinity chromatography followed by analysis with sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed a successive purification of the enzyme to homogeneity with a molecular size of 98 kilodaltons. Enzyme kinetics with glucose or 2-deoxyglucose (2-DG) as the substrate were measured spectrophotometrically by coupling the appropriate reactions to either NADPH or NAD+ formation. The Km of hexokinase with glucose as the substrate in the intracerebral glioma (0.138 mM) and subcutaneous glioma (0.183 mM) tissues was 2.1-2.7-fold higher than that observed in normal brain tissue (0.067 mM) (p less than 0.001). No significant differences were observed in the Km for hexokinase with 2-DG as the substrate in the glioma and normal brain tissue. The phosphorylation ratio for normal brain was 0.320 and was increased in the intracerebral glioma to 0.694 and in the subcutaneous glioma to 0.519. The ratios of deoxyglucose and glucose volumes of distribution in normal brain and intracerebral glioma tissues were 1.70 and 1.85, respectively. The lumped constants calculated directly from the phosphorylation ratios and the volumes of distribution of deoxyglucose and glucose were 0.517 in normal brain and 1.168 in intracerebral glioma. Our results indicate the lumped constant is increased 2.26-fold in intracerebral glioma compared with normal brain.
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PMID:Determination of the deoxyglucose and glucose phosphorylation ratio and the lumped constant in rat brain and a transplantable rat glioma. 272 62

The enzymes of glycolysis and selected enzymes of the pentose phosphate pathways were measured by fluorometric methods in extracts prepared from cultures of normal cortical human astrocytes and from cultures derived from low-grade (II) or high-grade (IV) gliomas. The hexokinase and phosphofructokinase levels of the low-grade glioma-derived line were not significantly different from those of the normal astrocyte cultures. However, the activities of hexokinase and phosphofructokinase were consistently and significantly increased in the high-grade glioma-derived lines. The activity of glucose-6-phosphate dehydrogenase was significantly decreased in all glioma-derived lines and by more than 90% in the high-grade-derived lines. Other enzymes of the glycolytic pathway were not significantly different from those of normal astrocytes, or they showed a variation inconsistently related to the neoplastic state. Glucose flux is not apparently regulated to a significant degree of hexokinase in glioma-derived lines, since the measured Vmax values are in substantial excess over the measured flux rates. Reversible binding of hexokinase to the particulate fraction was observed in both the normal astrocytes cultures and the high-grade glioma-derived lines. A twofold displacement of particulate hexokinase by ATP, ADP, 1-O-methylglucose, sorbitol-6-phosphate, and dibutyryl cyclic AMP was observed in the high-grade glioma-derived lines. The degree of displacement by various agents and the basal ratio of free/bound was not significantly different between the transformers and the nontransformants. The hexokinase from both the gliomas and the normal astrocytes was noncompetitively inhibited by the glucose analogue 2-deoxy-d-glucose. Phosphofructokinase activity is close to the observed glucose flux rates in both the normal astrocyte and the glioma-derived cultures. The phosphofructokinase activity of normal astrocytes is activated twofold or more by ADP, AMP, fructose-2,6-diphosphate, and Pi. However, these same ligands activate phosphofructokinase by less than twofold in a typical high-grade glioma-derived line. ATP, dibutyryl cyclic AMP, and citrate inhibit glioma and normal astrocytic phosphofructokinase, but the magnitude of the inhibition is much less than in the glioma-derived lines.
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PMID:Enzymes of glucose metabolism in cultured human gliomas: neoplasia is accompanied by altered hexokinase, phosphofructokinase, and glucose-6-phosphate dehydrogenase levels. 297 16

Positron emission computed tomographic (PECT) scanning studies have demonstrated that high grade gliomas exhibit increased 2-[18F]fluoro-2-deoxyglucose (18FDG) uptake compared to cerebral white matter and low grade gliomas. Hexokinase catalyzes the phosphorylation of glucose, as well as 18FDG and 2-deoxyglucose (2DG), thereby "trapping" these slowly metabolized analogues intracellularly. We hypothesize that a similar hexokinase-mediated uptake of glucose and glucose analogues occurs in vitro. Hexokinase activity was assayed in homogenates of tissue-cultured lines derived from high (IV) and low (II) grade gliomas and in fibroblasts derived from skin. With glucose as substrate, the maximal activity (Vmax) in the Grade IV lines was 200% of the activity found in the Grade II line, fibroblasts, and astrocytes; however, the Michaelis substrate affinity constant (Km) bore no relationship to tumor grade. With 2DG as substrate, the Vmax of all cell lines decreased, but the Grade IV lines still tended to have greater activity than the others. The Km values for 2DG were 5 times higher than those for glucose. Hexokinase is found in two subcellular compartments: an active form reversibly bound to mitochondria and a less active, cytosolic form. Up to 20% of the total hexokinase was found in the cytosol in all lines tested. High energy phosphate compounds (ATP, ADP, CTP, and others) displaced mitochondria-bound hexokinase, which increased the cytosolic form by 2-fold in the glioma lines, but fibroblast hexokinase distribution was unaffected. Our results suggest that: (a) high grade gliomas have increased hexokinase activity, which may explain the grade-related differences in 18FDG uptake observed by PECT scanning, and (b) human glioma hexokinases may be regulated by reversible subcellular compartmentation.
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PMID:Regulation of hexokinase in cultured gliomas. 387 50

Over 150 cases of central nervous system tumors have been studied with positron emission tomography using fluorine-18-labeled fluorodeoxyglucose (18FDG) as a tracer. From this material 100 consecutive cases of cerebral glioma have been reviewed and analyzed. The results show a strong correlation of tumor grade with glycolytic rate, with visual "hot spots" present in all high-grade neoplasms and in only four low-grade tumors. The quantitative accuracy is limited by three basic factors. First, the measurement of tissue uptake, as compared with the parent technique, autoradiography, is more difficult because detection must be done outside the body. Effects such as scattered radiation and self-attenuation introduce errors unless properly corrected. A more serious problem when measuring small structures, such as a rim-shaped high-grade glioma, is the limited spatial resolution. The most advanced scanner, the Neuro-PET, has a resolution of 6 to 7 mm. Second, corrections are needed for backflow, including free tracer at the time of the scan that will return to the blood and "trapped" tracer that will backflow because of the presence of phosphatase. These corrections are calculated from the blood activity using nominal rate constants for 18FDG. Our study found no significant alteration in rate constants between normal and tumoral tissue. Finally, a lumped constant is needed to correct for kinetic differences between 18FDG and glucose. If there is a change in the mechanism of either membrane transport or the hexokinase reaction, the lumped constant may change. However, measurements of actual glucose utilization in tissue culture lines from six patients support the 18FDG results.
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PMID:Issues in the in vivo measurement of glucose metabolism of human central nervous system tumors. 633 Dec 82


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