Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Some antitumor agents known to specifically inhibit certain tumor cell enzymes were examined for activity against glycolytic enzymes and growth of the insect trypanosomatid, Crithidia fasciculata. The cytoplasmic enzymes hexokinase, alpha-glycerophosphate dehydrogenase, malic dehydrogenase, and glucose-6-phosphate dehydrogenase were tested. Agaricic acid (2-hydroxy-1,2,3-nonadecane tricarboxylic acid) was highly inhibitory (50 to 100%) to malic and alpha-glycerophosphate dehydrogenases at approximately 3 x 10(-5)m; 2-(p-hydroxyphenyl)-2-phenylpropane (2 x 10(-4)m), and 5,6-dichloro-2-benzoxazolinone (5 x 10(-4)m) were less effective (50% inhibition) against them. The antiprotozoal agents primaquine (4 x 10(-4)m) and Melarsoprol (8 x 10(-4)m) were 30 to 40% inhibitory. Agaricic acid, 2-(p-hydroxyphenyl)-2-phenylpropane, and 5,6-dichloro-2-benzoxazolinone inhibited growth of Crithidia at less than 10(-4)m. Eight other test compounds from the Cancer Chemotherapy National Service Center (CCNSC) were not toxic to cell growth, although two (4-biphenylcarboxylic acid and 1-[p-chlorobenzyl]-2-ethyl-5-methyl-indole-3-acetic acid) inhibited Crithidia alpha-glycerophosphate dehydrogenase below 1 mm. All of the compounds used specifically inhibited cancer cell alpha-glycerophosphate dehydrogenase. The corresponding enzyme in pathogenic African trypanosomes is important in their terminal respiration. C. fasciculata may be useful in preliminary evaluation of chemotherapeutic agents as potential trypanocides.
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PMID:Effects of some antitumor agents on growth and glycolytic enzymes of the flagellate Crithidia. 578 78

The contents of mitochondrial inner membrane protein complexes were compared in normal liver and in Zajdela hepatoma mitochondria by the immunotransfer technique. Antibodies against core proteins 1 and 2, cytochrome c1, the iron-sulfur protein of Complex III, subunits I and II of cytochrome oxidase, and the alpha and beta subunits of the F1-ATPase were used. In addition, antibodies against a primary dehydrogenase, beta-hydroxybutyrate dehydrogenase, as well as the outer membrane pore protein were used. The results indicate that the components of the cytochrome chain and porin are greatly enriched in hepatoma mitochondria compared to normal rat liver mitochondria. This enrichment was also reflected in the rates of respiration in tumor mitochondria using a variety of substrates. Enrichment of porin may partially account for increased hexokinase binding to tumor mitochondria. In contrast to the respiratory chain components, the F1-ATPase and F0 (measured by DCCD binding) were not increased in tumor mitochondria. Thus, Zajdela hepatoma mitochondria components are nonstoichiometric, being enriched in oxidative capacity but relatively deficient in ATP synthesizing capacity. Finally, beta-hydroxybutyrate dehydrogenase, which is often decreased in hepatoma mitochondria, was shown here by immunological methods to be decreased by only 40%, whereas enzyme activity was less than 5% of that in normal rat liver.
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PMID:Immunochemical analysis of the membrane proteins of rat liver and Zajdela hepatoma mitochondria. 609 64

Glycolysis in Ehrlich ascites tumor cells suspended in buffer containing 5 mM Pi was 50% inhibited by ouabain. In the absence of Pi the inhibition was less striking. Permeabilization of the cells with filipin abolished glycolysis, but glycolysis was restored by addition of Pi and AMP. Neither ouabain nor quercetin inhibited glycolysis in these permeabilized cells. We conclude that quercetin did not inhibit hexokinase sufficiently to affect glycolysis. An extract of Ehrlich ascites tumor cells glycolyzed weakly unless either Pi or an ATPase (e.g. (Na+K+)-ATPase) was added. The low rate of glycolysis of the extract was even further reduced when an endogenous ATPase was removed by precipitation with CaATP. The glycolytic activity of this ATPase-deficient extract was restored by addition of purified (Na+K+)-ATPase or of CaATP-precipitable ATPase. Addition of hexokinase without Pi did not restore glycolytic activity to the extract. An explanation for the contradictory conclusions by Bustamante, E., Morris, H.P., and Pedersen, P.L. (J. Biol. Chem. (1981) 265, 8699-8704) is presented.
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PMID:The role of ATPase in glycolysis of Ehrlich ascites tumor cells. 621 95

The purpose of the present enzymic and histologic analysis of pulmonary samples from 39 subjects was to discern a common, meaningful pattern which may underlie the biochemical heterogeneity of lung neoplasms. The distribution among the different tumors of thymidine kinase, uridine kinase, phosphoserine phosphatase, hexokinase and adenylate kinase was found to correlate with each other. By averaging their standardized units (normal lung = 0) an enzymic index of neoplasticity was calculated for each tumor and used (in increasing order) to rank all 39. The index, showing a significant positive correlation with mitotic frequency, encompassed a continuous 100-fold range. Poorly differentiated carcinomas ranked high while neoplasms with better differentiation and prognosis placed in the lower half of the range. The results indicate that enzymes showing coordinated variations over a broad spectrum of tumors could contribute objective criteria to the rating of any individual tumor against a continuous, quantitative scale of neoplasticity.
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PMID:Enzyme pathology and the histologic categorization of human lung tumors: the continuum of quantitative biochemical indices of neoplasticity. 627 48

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

The experimental and theoretical bases for the use of Lonidamine in cancer therapy are reviewed and discussed. In murine tumors Lonidamine has a narrow spectrum of antitumor effects. It lacks the characteristic properties of antiproliferative drugs, as well as other important pharmacological actions, with the exception of antispermatogenic and embryotoxic effects which are closely related to the antitumor ones. Lonidamine appears not to affect the cell division processes. Available data instead show that it specifically affects the condensed or oxidized mitochondrion; since tumor cells have a mitochondrially bound hexokinase, both respiration and glycolysis are decreased. There is some evidence that hyperthermia, X rays and some chemotherapeutic agents, when used in combination with Lonidamine, increase the response of tumor cells or systems to this drug.
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PMID:Lonidamine, a new approach to cancer therapy. 637 44

The efflux of adenine nucleotides was studied in mitochondria isolated from normal rat liver, host livers, and the tumors from four Morris hepatoma lines of varying growth rates. [3H]Adenosine diphosphate (ADP) or [3H]adenosine triphosphate (ATP) was preloaded to the energized mitochondria, and the initial rates of exchange with unlabeled extramitochondrial nucleotides were measured with the carboxyatractyloside stop method. Results indicate that the Vmax values of ATP efflux in mitochondria from fast and intermediately growing tumors (hepatoma cell lines 7777, 7800, and 5123D) are significantly smaller than that of host or normal liver mitochondria, while in slow growing tumor (line 16) the Vmax is not different. On the other hand, for ADP efflux, the opposite (namely, higher in tumor than in host) is observed in the mitochondria of fast growing tumors. Preincubation with the divalent cation ionophore A23187 and calcium chelator ethyleneglycolbis(beta-aminoethyl ether)-N,N'-tetraacetic acid increases the efflux of both ATP and ADP (to a lesser extent) in these tumor mitochondria, indicating that the extraordinarily high concentrations of calcium form complexes with adenine nucleotides (particularly ATP) and thus lower the effective concentrations of free nucleotides for translocation. Together with previously published results (R. L. Barbour and S. H. P. Chan, Cancer Res., 43: 1511-1517, 1983) on lower nucleotide uptake rates in these tumor mitochondria, we propose that the lower ATP efflux and higher ADP efflux rates may cause a futile cycle of ADP transport across the mitochondrial membrane which may contribute to high rates of aerobic glycolysis (by stimulating key glycolytic enzymes such as hexokinase and phosphofructokinase) observed in these fast and intermediately growing tumors.
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PMID:Efflux of adenine nucleotides in mitochondria from rat tumor cells of varying growth rates. 646 6

Hypoxic cells in solid tumors are known to be resistant to radiation, and may also be resistant to some anti-cancer drugs. Biochemical properties of hypoxic cells, such as their dependence on anaerobic glycolysis leading to production of lactate and low pH might have potential for inhibition by drugs with selective activity against hypoxic cells. Such drugs might improve the Therapeutic Index when used with radiation or some conventional anti-cancer drugs. Preliminary studies have shown that the combination of hypoxia and low pH (pH 6.5-6.0) was cytotoxic to Chinese Hamster Ovary (CHO) cells incubated in vitro for up to 6 hours, although neither factor alone reduced plating efficiency. Lonidamine, an inhibitor of mitochondrially-bound hexokinase and lactate transport, was cytotoxic to CHO cells at low pH, but had no effect at physiological pH under aerobic or hypoxic conditions. Lonidamine has also been tested for in vivo effects against three murine tumors: the KHT fibrosarcoma, 16/C mammary carcinoma and the Lewis Lung Tumor. The drug was tested either alone, or with radiation or Adriamycin to kill aerobic cells, and/or with glucose and insulin to lower intra-tumor pH. No major therapeutic effects have been demonstrated.
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PMID:The effect of the drug lonidamine on Chinese hamster ovary cells in vitro and on experimental tumors. 648 Apr 46

The activities of six different enzymes were compared in 29 normal, 34 dysplastic, and 80 cancerous (both primary and metastatic) human breast tissues; in MCF-7 cells; and in primary rat mammary tumors. Benign lesions generally showed enzyme activities similar to those of normal breast tissues. Malignant tumors had significantly increased activities of lactate dehydrogenase (LDH), malate dehydrogenase (MDH), fructose-bisphosphate aldolase, hexokinase (HK), pyruvate kinase (PK), and creatine kinase. Enzyme activity in the malignant tumor was always higher than that in apparently normal or fibrocystic tissue from the same patient. Enzyme activities did not correlate with the levels of estrogen and progesterone receptors. LDH, MDH, and HK were elevated to a similar extent in all the tissues examined. Conversely, PK was elevated to a much greater extent in cancerous tissues, particularly in MCF-7 cells. The elevated activities of these enzymes may have diagnostic potential, especially when tumor tissue and apparently normal tissue from the same patient are compared.
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PMID:Enzyme activities in normal, dysplastic, and cancerous human breast tissues. 658 10

The activity, isoenzyme distribution and compartmentation of hexokinase (ADP: D-hexose-6-phosphotransferase, EC 2.7.1.1) were compared in slowly growing, well-differentiated medullary thyroid carcinoma (DMTC) and rapidly proliferating anaplastic thyroid carcinoma (AMTC) in the rat. Individual isoenzymes from either soluble or particulate fractions after solubilization were obtained by fast protein liquid chromatography and were kinetically analyzed either in soluble form or after (re)binding to rat liver mitochondria. These studies were undertaken to test the hypothesis that the growth rate of tumors is correlated with the activity of mitochondrial-bound hexokinase in our tumor system. In contradiction to this hypothesis, we found no difference in either enzyme activity or compartmentation of both kinds of tumors. The major part of enzyme activity was soluble (73 and 78% in DMTC and AMTC respectively). In addition, no major differences were observed in the kinetic properties of the individual isoenzymes of both tumors. Only soluble type II hexokinase from AMTC had a slightly decreased apparent Km for glucose. There appeared to be some differences in isoenzyme composition: both tumors contained type I and type II hexokinase in the soluble as well as in the particulate fractions. However, the proportion was shifted in favor of type II hexokinase in the soluble fraction of AMTC. Additional findings of this study were the following: the affinity of type II hexokinase to both substrates glucose and MgATP2- was significantly less compared to type I hexokinase. However, the inhibition constant for glucose-1,6-diphosphate of both isoenzymes was exactly the same. The bound form of both isoenzymes had the same substrate affinities as the soluble form but was considerably less inhibited by glucose-1,6-diphosphate. In the latter respect, type I and type II hexokinase behaved in the same way.
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PMID:Hexokinase isoenzymes from anaplastic and differentiated medullary thyroid carcinoma in the rat. 661 Dec 65


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