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)

The activity of 19 enzymes (hexokinase, glucoso-6-phosphatisomerase, alpha-glycerophosphate-, lactate-, succinate-, isocitrate-, malate-, glucoso-6-phosphate-, 6-phosphogluconate-, glutamate-, alcohol-, inosine-5'-phosphate-, guanosine-5'-monophosphate-dehydrogenase, cytochromoxidase NAD.N2- and NADP.N2-diaphorase, monoaminoxidase, alkaline and acid phosphatase) was studied comparatively in the mucosa of control rats and in tumors of the small intestine (27), and large intestine (176), induced in 41 rats percutaneously by 1,2-dimethylhydrazine. A decreased level of the enzymes of tissue respiration and Krebs cycle was found with a simultaneous increase in the activity of the enzymes of glycolysis and pentoso-monophosphate shunt. These data evidence variations in tumor metabolism consisting in oxidizing phosphorylation, being replaced by aerobic glycosis, and also reflecting an intensive proliferation of tumor cells.
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PMID:[An enzymohistochemical study of experimental tumors of the intestine]. 123 60

1. The reoxidation of cytosolic NADH was studied in a line of human hepatoma cells (HuH13) whose mitochondria preferentially utilized glutamine for ATP formation. 2. The tumor cells showed mitochondrial reoxidation of NADH, as evidenced by the accumulation of pyruvate, when incubated aerobically with L-lactate. The involvement of the respiratory chain was demonstrated by the addition of specific inhibitors. 3. Glutamine oxidation proceeded in the tumor mitochondria exclusively via a pathway involving transamination. Malate stimulated aspartate production from glutamine. 4. When the tumor cells were cultured in Eagle's medium with aminooxyacetate or in the absence of glutamine, a marked reduction in the cellular NAD/NADH ratio was observed. 5. These results indicate that the malate-aspartate shuttle was functioning in the tumor cells.
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PMID:Oxidation of cytosolic NADH by the malate-aspartate shuttle in HuH13 human hepatoma cells. 131 Feb 90

Deletion mutagenesis in human NAD(P)H:Quinone Oxidoreductase (NQO1) gene and transfection studies into mammalian cells identified a segment of DNA designated as human Antioxidant Response Element (hARE) responsible for high basal expression in tumor cells and its induction by beta-naphthoflavone (beta-NF). The twenty four base pairs of the hARE contains an essential cis-element AP1 binding site and has been shown to bind to jun-D and c-fos proteins from mouse hepatoma (Hepa-1) nuclear extract. In the present report, we have identified jun-B as the third major protein in the hARE-Hepa-1 proteins complex observed in the band shift assays.
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PMID:Identification of jun-B as third member in human antioxidant response element-nuclear proteins complex. 144 67

The major soluble protein of bovine cornea (BCP 54: bovine corneal protein 54 kDa) was isolated successively by gel filtration, anion-exchange chromatography and chromatofocusing. The amino acid sequence of a fragment of the purified BCP 54 obtained by lysyl-endopeptidase digestion showed marked homology with tumor-associated and 2,3,7,8-tetrachloro-dibenzo-p-dioxin-inducible aldehyde dehydrogenase (AIDH). From the high similarity of BCP 54 with tumor-associated AIDH in structural form, it is suggested that BCP 54 has AIDH activity. We confirmed a high AIDH activity of BCP 54 by immunoprecipitation using a mouse anti-BCP 54 monoclonal antibody followed by a spectrophotometric assay for AIDH activity. Next we demonstrated the unique properties of the purified BCP 54 as AIDH. The major isoelectric point is 6.41. BCP 54 preferentially oxidizes aromatic aldehyde such as benzaldehyde with NAD as coenzyme, but cannot oxidize phenylacetaldehyde. After heat treatment the AIDH activity is more stable with propionaldehyde-NAD than with benzaldehyde-NADP. With propionaldehyde-NAD the pH profile shows a broad plateau from pH 6-9 followed by a sharp rise up to pH 10. In contrast, with benzaldehyde-NADP there is a sharp optimum at pH 9.0. The activity with only benzaldehyde-NADP is inhibited by p-hydroxymercuribenzoate, but is not affected by disulfiram and diethylstilbestrol. So we suggested that BCP 54 is an AIDH with kinetic properties different from the rat tumor-associated AIDH.
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PMID:Kinetic properties of the bovine corneal aldehyde dehydrogenase (BCP 54). 148 3

As a common characteristic of tumor cells, as well as of normal proliferating cells in the G1-phase of cell cycle, one finds constitutive high levels of all the glycolytic metabolites arising between glucose 6-phosphate and phosphoenolpyruvate. Thus, it is that the phosphometabolites fructose 1,6-bisphosphate, ribose 5-P, P-ribose-PP, NAD, GTP, CTO, UTP, UDP-glucose, glycerol 3-P, glycerol phosphocholine and glycerol phosphoethanolamine are useful in the 31P-nuclear magnetic resonance (NMR) detection of solid tumors in animals and man. This expansion of phosphometabolites is achieved during tumor formation as a result of reductions in levels of enzymes degrading phosphometabolites, owing to the decline in the glycerol 3-P hydrogen shuttle, and as a consequence of alterations in the glycolytic isoenzyme equipment. Tumor cells typically express a particular isoenzyme of pyruvate kinase called type M2 (K) at high levels. This isoenzyme is subject to a complex regulation by amino acids, by fructose 1,6-bisphosphate, and by hormonal- and oncogene-dependent phosphorylation. Pyruvate kinase type M2 is a substrate for the oncogene encoded PP60v-src-tyrosine kinase. A drastic decrease in the affinity for its substrate phosphoenolpyruvate found after transformation by the src-oncogene can be explained as a consequence of the phosphorylation of pyruvate kinase in serine and tyrosine. These phosphorylations induce the breakdown of tetrameric pyruvate kinase to the trimeric and dimeric forms. Unlike the tetrameric form, the dimeric form as a low affinity for phosphoenolpyruvate. Partial inactivation of pyruvate kinase and enolase on the one hand, and a hyperactivation of hexokinase and phosphofructokinase on the other hand, lead to an expansion of all metabolites. Only when these metabolites attain high levels, thereby assuring a sufficient supply of metabolites for RNA, DNA, lipid, and complex carbohydrate synthesis, can cell proliferation proceed. This accumulation of metabolites in the G1-phase cells has been termed a "metabolic budget system" because it senses not only the actual nutrient levels, but also the supply over a period of time. Monoclonal antibodies specific for the dimeric form of pyruvate kinase type M2 can be used for the immunohistological detection of tumor cells. The amount of the dimeric form in tumor cells closely correlates with the degree of malignancy and can be used for a nonspecific detection of tumors based on assays performed with patient's plasma.
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PMID:Double role for pyruvate kinase type M2 in the expansion of phosphometabolite pools found in tumor cells. 153 31

A therapeutic dose of labelled 5-fluorouracil (5-FU) was infused via the hepatic artery during 30 min with or without ligation of the left portal venous branch in Wistar rats with a secondary liver cancer in the left lateral lobe. After another 60 min, the incorporation of 5-FU into the acid soluble fraction (ASF), ribonucleic acid (RNA) and deoxyribonucleic acid (DNA), was determined in tumor, ligated and unligated liver lobes, small intestine, kidney, and bone marrow. The liver nucleotide profile was examined with isotachophoresis. Portal venous branch ligation (PVBL) caused the following changes, compared with the unligated control group: in the tumor, the incorporation of 5-FU into RNA and DNA decreased and the ratio RNA/acid-soluble fraction labelling decreased. The incorporation increased in intestinal and bone marrow RNA. It was unchanged in liver and kidney. The ratio of tumor to peripheral normal-tissue (small intestine, bone marrow, and kidney) labelling of RNA and DNA decreased. Liver nucleotides (F)UTP, (F)UDP-glucuronic acid, (F)UDP-N-acetylhexosamine, and NAD were lower in the ligated than in the unligated liver lobe. ATP and energy charge did not decrease significantly. In conclusion, PVBL in conjunction with hepatic arterial administration of 5-FU increased systemic drug exposure and possibly decreased hepatic tumor anabolism. It has not been examined how this interferes with the therapeutic effect.
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PMID:Incorporation of 5-fluorouracil into rat liver tumor and normal tissues and the liver nucleotide profile after administration by the hepatic artery during portal venous branch ligation. 157 Apr 10

Kinetic studies of Morris 7777 hepatoma mitochondrial NAD(P) malic enzyme were consistent with an ordered mechanism where NAD adds to the enzyme before malate and dissociation of NADH from the enzyme is rate-limiting. In addition to its active site, malate apparently also associates with a lower affinity with an activator site. The activator fumarate competes with malate at the activator site and facilitates dissociation of NADH from the enzyme. The ratio of NAD(P) malic enzyme to malate dehydrogenase activity in the hepatoma mitochondrial extract was found to be too low, even in the presence of known inhibitors of malate dehydrogenase, to account for the known ability of NAD(P) malic enzyme to intercept exogenous malate from malate dehydrogenase in intact tumor mitochondria (Moreadith, R.W., and Lehninger, A.L. (1984) J. Biol. Chem. 259, 6215-6221). However, NAD(P) malic enzyme may be able to intercept exogenous malate because according to the present results, it can associate with the pyruvate dehydrogenase complex, which could localize NAD(P) malic enzyme in the vicinity of the inner mitochondrial membrane. The activity levels of some key metabolic enzymes were found to be different in Morris 7777 mitochondria than in liver or mitochondria of other rapidly dividing tumors. These results are discussed in terms of differences among tumors in their ability to utilize malate, glutamate, and citrate as respiratory fuels.
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PMID:Kinetics and regulation of hepatoma mitochondrial NAD(P) malic enzyme. 158 26

One-electron reduction of diaziquone (AZQ) by purified rat liver NADPH cytochrome c reductase was associated with formation of AZQ semiquinone, superoxide anions, hydrogen peroxide, and hydroxyl radicals as indicated by ESR spin-trapping studies. Reactive oxygen formation correlated with AZQ-dependent production of single and double PM2 plasmid DNA strand breaks mediated by this system as detected by gel electrophoresis. Direct two-electron reduction of AZQ by purified rat liver NAD(P)H (quinone acceptor) oxidoreductase (QAO) was also associated with formation of AZQ semiquinone, superoxide anions, hydrogen peroxide, and hydroxyl radicals as detected by ESR spin trapping. Furthermore, PM2 plasmid DNA strand breaks were detected in the presence of this system. Plasmid DNA strand breakage was inhibited by dicumarol (49 +/- 5%), catalase (57 +/- 2.3%), SOD (42.2 +/- 3.6%) and ethanol (41.1 +/- 3.9%) showing QAO and reactive oxygen formation was involved in the PM2 plasmid DNA strand breaks observed. These results show that both one- and two-electron enzymatic reduction of AZQ give rise to formation of reactive oxygen species and DNA strand breaks. Autoxidation of the AZQ semiquinone and hydroquinone in the presence of molecular oxygen appears to be responsible for these processes. QAO appears to be involved in the metabolic activation of AZQ to free radical species. The cellular levels and distribution of this enzyme may play an important role in the response of tumor and normal cells to this antitumor agent.
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PMID:Free radical formation and DNA strand breakage during metabolism of diaziquone by NAD(P)H quinone-acceptor oxidoreductase (DT-diaphorase) and NADPH cytochrome c reductase. 166 2

The phenotypic expression of multidrug resistance by the doxorubicin-selected AdrR human breast tumor cell line is associated with overexpression of plasma membrane P-170 glycoprotein and increased cytosolic selenium-dependent GSH-peroxidase activity relative to the parental MCF-7 wild-type line (WT). To determine whether doxorubicin resistance by AdrR cells persists in vivo, and to further investigate the possibility of biochemical differences between WT and AdrR solid tumors, both tumor cell lines were grown as subcutaneous xenografts in athymic nude mice. Tumorigenicity depended upon cell inoculation burden, and tumor incidence was similar for both cell lines (greater than 80% tumor takes at 10(7) cells/mouse) at 14 days, provided 17 beta-estradiol was supplied to the animals bearing the WT tumors. However, the growth rate for the AdrR xenografts was only about half that of WT xenografts. Doxorubicin (2-8 mg/kg, i.p., injected weekly) significantly diminished the growth of the WT tumors, but AdrR solid tumors failed to respond to doxorubicin. The accumulation of 14C-labeled doxorubicin was 2-fold greater in WT xenografts that in AdrR, although there were no differences in host organ drug levels in mice bearing either type of tumors. Membrane P-170 glycoprotein mRNA was detected by slot-blot analysis in the AdrR tumors, but not in WT. Electron spin resonance 5,5-dimethylpyrroline-N-oxide-spin-trapping experiments with microsomes and mitochondria from WT and AdrR xenographs demonstrated a 2-fold greater oxygen radical (superoxide and hydroxyl) formation from activated doxorubicin with WT xenographs compared to AdrR. Selenium-dependent glutathione (GSH)-peroxidase, superoxide dismutase and GSH-S-aryltransferase activities in AdrR xenografts were elevated relative to WT. Although the activities of the latter two enzymes were similar to those measured in both tumor cell lines, GSH-peroxidase activities were elevated 70-fold (WT) and 10-fold (AdrR) in xenografts compared to tumor cells. In contrast, in both WT and AdrR solid tumors in vivo, catalase, NAD(P)H-oxidoreductases, and glutathione disulfide (GSSG)-reductase activities, and GSH and GSSG levels were not markedly different, and were essentially the same as in cells in vitro. Like the MDR cells in culture, AdrR tumor xenografts were extremely resistant to doxorubicin and retained most of the characteristics of the altered phenotype. These results suggest that WT and AdrR breast tumor xenografts provide a useful model for the study of biochemical and pharmacological mechanisms of drug resistance by solid tumors in vivo.
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PMID:Biochemical and pharmacological characterization of MCF-7 drug-sensitive and AdrR multidrug-resistant human breast tumor xenografts in athymic nude mice. 167 69

Exposure of Ehrlich ascites tumor cells to 3-aminobenzamide for 60 min resulted in a dose-dependent increase of cellular NAD and ATP levels at a concentration range of 0.3-5 mM. In the cells exposed to 5-methylnicotinamide there was a decrease of both nucleotide levels. As a possible cause for these changes we found a marked inhibition of microsomal NAD glycohydrolase activity by 3-aminobenzamide and a moderate stimulation of this enzyme by 5-methylnicotinamide. Furthermore, 3-aminobenzamide significantly enhanced the cellular uptake of nicotinamide and NAD synthesis, probably by the stimulation of nuclear ATP-NMN adenylyltransferase activity. We show also that the cells containing elevated NAD and ATP levels by the exposure to 3-aminobenzamide became resistant to the 5-azacytidine cytotoxicity.
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PMID:Influence of ADP-ribosyltransferase inhibitors on the intracellular NAD and ATP levels in Ehrlich ascites tumor cells: implication for the altered NAD + ATP-dependent cellular sensitivity to the cytotoxic agents. 169 42


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