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)

Resistance of hypoxic tumor cells to ionizing radiation and cytotoxic drugs has been attributed to changes in the reactivity and/or the half-times of reactive species in the altered redox environment. Exposure of eukaryotic cells to such hypoxic conditions results in the induction of the synthesis of several unrelated proteins. To investigate further the phenomenon of hypoxic cell resistance to cytotoxic drugs, we examined the effects of hypoxia on the expression of a group of enzymes involved in drug metabolism. Exposure of HT29 colon carcinoma cells to hypoxia resulted in a marked increase in the activity of DT-diaphorase and in glutathione content. The activity of glutathione transferase was not increased by this treatment. The response was proportional to the duration of hypoxia. After the cells were exposed to hypoxic conditions for 8 h, followed by restoration of an oxic environment, the elevation in enzyme activity and glutathione content reached a peak at 48 h (40 h after the restoration of an oxic environment) and returned to baseline at 72 h. Elevation of steady-state levels of DT-diaphorase and gamma-glutamylcysteine synthetase mRNA followed a similar time course, with > 10-fold increases over oxic cells at 24 h. The elevation of DT-diaphorase mRNA content was found to result both from transcriptional induction and from increased message stability. The magnitude and persistence of elevated detoxicating enzyme activity following a relatively short hypoxic exposure followed by reoxygenation suggest a novel potential mechanism of resistance to cytotoxic drugs in hypoxic tumors.
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PMID:Effects of hypoxia on detoxicating enzyme activity and expression in HT29 colon adenocarcinoma cells. 820 21

The levels of NAD(P)H:(quinone-acceptor) oxidoreductase (EC.1.6.99.2) (DT-diaphorase) mRNA and enzyme activity have been studied in paired human normal lung and non-small cell lung tumor samples from patients with a history of cigarette smoking. There were significantly higher levels of DT-diaphorase mRNA (1.2 kilobases) in lung tumor compared to normal lung tissue of patients who had stopped smoking more than 6 months before surgery, with relative values (normalized to beta-actin mRNA) of 29.6 +/- 7.8 (SE) in the lung tumor compared to 11.7 +/- 2.2 in normal lung tissue (P < 0.05). There was no significant difference in DT-diaphorase mRNA between lung tumor and normal lung tissue of subjects who were smokers at the time of surgery, with values of 16.5 +/- 2.1 and 15.3 +/- 2.5 (P > 0.05), respectively. DT-diaphorase enzyme activity in normal and tumor lung tissue was positively correlated with DT-diaphorase mRNA (r = 0.908, P < 0.01). The results of the study suggest that DT-diaphorase does not function as an inducible protectant enzyme in human lung against oxidant species and carcinogens present in cigarette smoke. Metabolism of some anticancer drugs by DT-diaphorase can alter their activity. Differences in DT-diaphorase between lung tumors of smokers and past smokers might alter the response to these drugs.
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PMID:Cigarette smoking is a determinant of DT-diaphorase gene expression in human non-small cell lung carcinoma. 822 86

An L5178Y murine lymphoblast cell line resistant to 3'-(3-cyano-4-morpholinyl)-3'-deaminoadriamycin (MRA-CN), L5178Y/MRA-CN, was isolated and characterized. L5178Y/MRA-CN cells were 9.6-fold resistant to MRA-CN compared with parental cells. The resistant cell line also displayed 2-fold resistance to 3'-(4-morpholinyl)-3'-deaminoadriamycin but was not cross-resistant to Adriamycin or chlorambucil. Uptake of MRA-CN was slightly reduced in the resistant cells compared to sensitive cells, but the distribution of the drug within the cells was unchanged. DNA interstrand cross-linking by MRA-CN was not significantly different in the sensitive and resistant cell lines, but MRA-CN was slightly less effective in inhibiting both DNA and RNA synthesis in L5178Y/MRA-CN cells compared with parental cells. NADPH cytochrome P-450 reductase activity was increased in L5178Y/MRA-CN cells compared to parental cells, while the activity of DT-diaphorase was decreased in the resistant cells. The levels of glutathione and glutathione S-transferase activity were increased in the resistant cells compared to sensitive cells; however, pretreatment of L5178Y/MRA-CN cells with buthionine sulfoximine to reduce the glutathione level did not reverse the resistance of these cells to MRA-CN. MRA-CN induced DNA fragmentation that was characteristic of apoptosis in both L5178Y and L5178Y/MRA-CN cells at equitoxic drug concentrations. However, apoptosis occurred more rapidly in L5178Y/MRA-CN cells compared with parental cells. Thus, MRA-CN induces apoptosis in L5178Y cells, and this effect may be important for the anti-tumor activity of this agent. In contrast, DNA interstrand cross-linking does not appear to be the primary mechanism responsible for the cytotoxicity of MRA-CN in these cells.
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PMID:Activity of 3'-(3-cyano-4-morpholinyl)-3'-deaminoadriamycin in sensitive and resistant L5178Y lymphoblasts in vitro. 827 85

The effect of pH and oxygen on DNA alkylation by mitomycin C (MMC) was studied with cell fractions and intact cells. The cell lines used were the HCT 116 human colon cancer cell line and a MMC-resistant subline (HCT 116-R30A) that has 5% of the quinone reductase activity present in the parent cell line. Microsomal fractions of the two cell lines catalyzed MMC-DNA adduct formation only under anaerobic conditions with equal efficiency. However, the pH of the reaction controlled the production of four identified and two unidentified adducts. Soluble fractions from each cell source catalyzed MMC-DNA adduct formation under aerobic and anaerobic conditions similarly. At higher pH, limited DNA adducts were produced by MMC activated by soluble fractions from either cell source. At lower pH, more DNA adducts were obtained with MMC activated by the soluble fraction of HCT 116 cells than with that activated by the soluble fraction of HCT 116-R30A cells. Four of these adducts were identified as N2-(2" beta,7"-diaminomitosene-1" alpha-yl)-2'-deoxyguanylic acid, N2-(2" beta,7"-diaminomitosen-1" beta-yl)-2'-deoxyguanylic acid, N2-(10"-decarbamoyl-2",7"-diaminomitosen-1" alpha-yl)-2'-deoxyguanylic acid, and N2-(2" beta,7"-diamino-10"-deoxyguanyl-N2-yl-mitosen-1" alpha-yl)-2'- deoxyguanylic acid. Acidic intracellular pH enhanced the cytotoxicity of MMC for HCT 116 cells, decreasing the IC50 from 0.3 +/- 0.04 microM to 0.1 +/- 0.03 microM, but pH had limited effect on the cytotoxicity of MMC for HCT 116-R30A cells. When intracellular pH was decreased, interstrand DNA cross-linking by MMC increased to a greater extent in HCT 116 cells than in HCT 116-R30A cells. Only two DNA adducts, each at low intensity, were detected in HCT 116-R30A cells treated at pH 6.0 and 7.6 and in HCT 116 cells treated at pH 7.6. However, six radioactive spots were detected in HCT 116 cells treated at pH 6.0. Three of these adducts were identified. This is the first direct evidence that acidic intracellular pH enhances MMC-DNA adduct formation in tumor cells containing high quinone reductase activity. Results from this study further confirm that pH and not enzyme is the determining factor in the distribution of types of MMC-DNA adducts. This study also indicates that low intracellular pH enhances the activity of quinone reductase in reducing MMC, which is important for aerobic cytotoxicity of MMC against tumor cells with high concentration of quinone reductase.
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PMID:Enzymatic and pH modulation of mitomycin C-induced DNA damage in mitomycin C-resistant HCT 116 human colon cancer cells. 831 19

It has been reported that several naturally occurring and related synthetic organosulfur compounds exert chemopreventive effects in several target organs in rodent models. The chemopreventive actions of 40 and 80% maximum tolerated doses (MTD) of organosulfur compounds, namely anethole trithione, diallyl disulfide, N-acetylcysteine, and taurine, administered in AIN-76A diet, on azoxymethane (AOM)-induced neoplasia were investigated in male F344 rats. Also, the effects of these agents on the activities of phase II enzymes, namely glutathione S-transferase (GST), NAD(P)H-dependent quinone reductase, and UDP-glucuronosyl transferase, in the liver and colonic mucosa and tumors were assessed. The MTD levels of anethole trithione, diallyl disulfide, N-acetylcysteine, and taurine were determined in male F344 rats and found to be 250, 250, 1500, and 1500 ppm, respectively. At 5 weeks of age, animals were fed the control diet (AIN-76A) or experimental diets containing 40 or 80% MTD levels of each test agent. All animals in each group, except those allotted for vehicle (saline) treatment, were administered AOM s.c. at a dose rate of 15 mg/kg body weight once weekly for 2 weeks. All animals were necropsied during week 52 after the second AOM injection. Colonic mucosal and tumor and liver enzyme activities were measured in animals fed 80% MTD levels of each test agent. Colon tumors were subjected to histopathological evaluation and classified as invasive or noninvasive adenocarcinomas. Colon tumor incidence (percentage of animals with tumors) and tumor multiplicity (tumors/animal) were compared among various dietary groups. The results indicated that administration of 200 ppm (80% MTD) anethole trithione significantly inhibited the incidence and multiplicity of both invasive and noninvasive adenocarcinomas, whereas feeding of 100 ppm (40% MTD) anethole trithione or 100 (40% MTD) or 200 ppm (80% MTD) diallyl disulfide suppressed only invasive adenocarcinomas of the colon. Although diets containing N-acetylcysteine and taurine inhibited colon tumor multiplicity, the effect was somewhat marginal. GST, NAD-(P)H-dependent quinone reductase, and UDP-glucuronosyl transferase activities in colonic mucosa and tumor and liver were significantly elevated in animals fed anethole trithione or diallyl disulfide, compared to those fed the control diet. N-Acetylcysteine and taurine slightly but significantly increased only the GST activity in the liver. Although other mechanisms are not excluded, inhibition of AOM-induced colon carcinogenesis by anethole trithione and diallyl disulfide may be associated, in part, with increased activities of phase II enzymes such as GST, NAD(P)H-dependent quinone reductase, and UDP-glucuronosyl transferase in the liver and colon.
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PMID:Chemoprevention of colon carcinogenesis by organosulfur compounds. 833 52

NAD(P)H:Quinone Oxidoreductase1 (NQO1) also known as DT-diaphorase is a flavoprotein that catalyzes the two-electron reduction of quinones, quinone imines and azo-dyes and thereby protects cells against mutagenicity and carcinogenicity resulting from free radicals and toxic oxygen metabolites generated by the one-electron reductions catalyzed by cytochromes P450 and other enzymes. High levels of NQO1 gene expression have been observed in liver, lung, colon and breast tumors as compared to normal tissues of the same origin. The transcription of the NQO1 gene is activated in response to exposure to bifunctional (e.g. beta-naphthoflavone (beta-NF), 2, 3, 7, 8 tetrachorodibenzo-p-dioxin (TCDD)) and monofunctional (phenolic antioxidants/chemoprotectors e.g. 2(3)-tert-butyl-4-hydroxy-anisole (BHA)) inducers. The high level of expression of the NQO1 gene and its induction by beta-NF and BHA require the presence of an AP1 binding site contained within the human Antioxidant Response Element (hARE) and are mediated by products of proto-oncogenes, Jun and Fos. Induction of NQO1 gene expression involves transfer of a redox signal from xenobiotics to unknown 'redox protein(s)' which in turn, modify the Jun and Fos proteins for greater affinity towards the AP1 site of the NQO1 gene and activates transcription. The expression and regulation of the NQO1 gene is complex as many additional cis-elements have been identified in the promoter region and is a subject of great future interest. In addition to established tumors, NQO1 gene expression is also increased in developing tumors, indicating a role in cellular defense during tumorigenesis. It has been proposed that low molecular weight substance(s) can diffuse from tumor cells into surrounding normal cells and activate the expression of the NQO1 gene. Purification and characterization of such substance(s) may provide important information in regard to the mechanism of activation of NQO1 gene expression and the role of increased NQO1 expression in tumor development. In view of the general consensus that NQO1 is over-expressed in tumor cells and the realization that NQO1 may either activate or detoxify xenobiotics, it is important to establish the role of NQO1 in the activation, and the detoxification of xenobiotics and drugs and in the intrinsic sensitivity of tumors to bioreductive alkylating aziridinyl benzoquinones such as diaziquone (AZQ), mitomycin C (MMC), and indoloquinone EO9, as well as to the dinitrophenyl aziridine, CB1954, and the benzotriazine-di-N-oxide, SR 4233.
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PMID:NAD(P)H:quinone oxidoreductase1 (DT-diaphorase) expression in normal and tumor tissues. 837 15

Using 4 human cancer cell lines, 4 tumors xenografted into nude mice, and 11 fresh tumor specimens removed at surgery, we investigated the relevance of NAD(P)H:quinone oxidoreductase (DT-diaphorase, DTD) activity (nmoles/min/mg protein) to mitomycin C (MMC)-induced cytotoxicity. In culture cell lines, KB cells had significantly higher levels of DTD activity (8260) than PH101 (1934), SH101 (1805) or K562 (1796), and the highest sensitivity to MMC. In contrast, the higher the DTD activity of xenografts, the greater their resistance to MMC, while the inhibition rate of relative tumor growth for MMC, as evaluated by the NCI protocol, was highest in SH-6, high in CH-5, lower in CH-4 and lowest in EH-6. The investigation using 11 fresh tumor specimens also showed an inverse relationship between IC50 values after a 30-min MMC treatment, as evaluated by ATP assay and DTD activities. Moreover, a non-toxic DTD inhibitor, dicoumarol (DIC), or flavin adenine dinucleotide (FAD), suppressed the efficacy of MMC in culture cells, but enhanced it in xenografts. Thus, we suggest that DTD may play an important role in MMC-induced cytotoxicity but MMC metabolism by DTD in solid tumors may differ from that in culture cells.
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PMID:Relevance of DT-diaphorase activity to mitomycin C (MMC) efficacy on human cancer cells: differences in in vitro and in vivo systems. 847 41

Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione], a substituted 1,2-dithiole-3-thione, protects against the acute and chronic toxicities of many xenobiotics and prevents chemically induced carcinogenicity in several target organs of rodents. The effects of dietary oltipraz, fed during the initiation and postinitiation stages, on azoxymethane-induced colon carcinogenesis and on the levels of several detoxifying enzymes, namely, glutathione S-transferase, NAD(P)H:quinone reductase, and UDP-glucurinyl transferase activities, were studied in male F344 rats. At 5 weeks of age, groups of animals were fed the control diet (modified AIN-76A diet) or a diet containing 200 ppm (40% maximum tolerated dose) of oltipraz. At 7 weeks of age, all animals except those in the vehicle (normal saline solution)-treated groups were given two weekly s.c. injections of azoxymethane at a dose of 15 mg/kg body weight. Three days after the second injection of azoxymethane, the groups of animals fed the oltipraz diet were transferred to the control diet (termed the initiation period) and the groups of animals receiving the control diet were transferred to the oltipraz diet (termed the postinitiation period). All groups were continued on this regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Intestinal tumors were evaluated histopathologically using routine procedures. Liver, colonic mucosa, and tumors were analyzed for glutathione S-transferase, NAD(P)H:quinone reductase, and UDP-glucurinyl transferase activities. The results indicate that oltipraz administered during the initiation stage significantly inhibited the incidence and multiplicity of invasive adenocarcinomas of the colon (P < 0.001), as well as the multiplicity of invasive and noninvasive adenocarcinomas (P < 0.01). Feeding of oltipraz during the postinitiation phase completely suppressed the formation of invasive adenocarcinomas (P < 0.0001) and significantly inhibited the formation of noninvasive and total adenocarcinomas, as well as the multiplicity (tumors/tumor-bearing animal, P < 0.001). Furthermore, oltipraz significantly suppressed the tumor volume when administered during the initiation phase (> 80%) or the postinitiation (> 93%) phase. Animals fed the oltipraz diet during the postinitiation stage showed increased levels of glutathione S-transferase, NAD(P)H:quinone reductase, and UDP-glucurinyl transferase activities (2-6-fold). Although the precise mechanism by which oltipraz inhibits colon tumor initiation and/or promotion remains to be elucidated, it is likely that the effect during the initiation stage may be due to an alteration of carcinogen metabolism.
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PMID:Chemopreventive effect of oltipraz during different stages of experimental colon carcinogenesis induced by azoxymethane in male F344 rats. 849 12

In recent years we and others have shown the cancer chemopreventive effects of green tea in several animal tumor models. In this study we assessed the cancer chemopreventive effects of water extract of green tea (WEGT) and the polyphenolic fraction (GTP) isolated from WEGT against N-nitrosodiethylamine (DEN)- and benzo[a]pyrene (BP)-induced forestomach and lung tumorigenesis in A/J mice. The protective effects, both in forestomach and lungs, were evident by a decrease in number of tumors and the percentage of mice with tumors when WEGT and GTP were fed to animals during initiation, post-initiation and entire period of tumorigenesis protocols. Oral feeding of 0.2% GTP in drinking water to mice afforded 68-82 and 39-66% protection against DEN- and BP-induced forestomach tumorigenesis respectively. In case of pulmonary tumor multiplicity caused by DEN and BP, the protective effects of GTP were between 38-43 and 25-46% respectively. Similarly, oral feeding of 2.5% WEGT to mice also afforded 80-85 and 61-71% protection against DEN- and BP-induced forestomach tumorigenesis respectively. In case of lung tumorigenesis, the protective effects of WEGT were 43-62 and 25-51% respectively. Histological studies of forestomach tumors showed significantly lower squamous cell carcinoma counts in GTP- and WEGT-fed groups of mice compared to carcinogen alone treated control group of mice. When pulmonary tumors were examined histologically, no adenocarcinomas were observed in GTP- and WEGT-fed groups of mice compared to 20% mice with adenocarcinomas in carcinogen alone treated control group. Oral feeding of GTP and WEGT in drinking water also showed significant enhancement in the activities of glutathione S-transferase and NADP(H): quinone reductase in liver, small bowel, stomach and lung. The results of this study suggest that green tea possesses chemopreventive effects against carcinogen-induced tumorigenesis in internal body organs, and that the mechanism of such effects may involve the enhancement of phase II and anti-oxidant enzyme systems.
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PMID:Protection against N-nitrosodiethylamine and benzo[a]pyrene-induced forestomach and lung tumorigenesis in A/J mice by green tea. 850 76

This article summarizes available data on the chemopreventive efficacies of tea polyphenols, curcumin and ellagic acid in various model systems. Emphasis is placed upon the anticarcinogenic activity of these polyphenols and their proposed mechanism(s) of action. Tea is grown in about 30 countries and, next to water, is the most widely consumed beverage in the world. Tea is manufactured as either green, black, or oolong; black tea represents approximately 80% of tea products. Epidemiological studies, though inconclusive, suggest a protective effect of tea consumption on human cancer. Experimental studies of the antimutagenic and anticarcinogenic effects of tea have been conducted principally with green tea polyphenols (GTPs). GTPs exhibit antimutagenic activity in vitro, and they inhibit carcinogen-induced skin, lung, forestomach, esophagus, duodenum and colon tumors in rodents. In addition, GTPs inhibit TPA-induced skin tumor promotion in mice. Although several GTPs possess anticarcinogenic activity, the most active is (-)-epigallocatechin-3-gallate (EGCG), the major constituent in the GTP fraction. Several mechanisms appear to be responsible for the tumor-inhibitory properties of GTPs, including enhancement of antioxidant (glutathione peroxidase, catalase and quinone reductase) and phase II (glutathione-S-transferase) enzyme activities; inhibition of chemically induced lipid peroxidation; inhibition of irradiation- and TPA-induced epidermal ornithine decarboxylase (ODC) and cyclooxygenase activities; inhibition of protein kinase C and cellular proliferation; antiinflammatory activity; and enhancement of gap junction intercellular communication. Curcumin is the yellow coloring agent in the spice tumeric. It exhibits antimutagenic activity in the Ames Salmonella test and has anticarcinogenic activity, inhibiting chemically induced preneoplastic lesions in the breast and colon and neoplastic lesions in the skin, forestomach, duodenum and colon of rodents. In addition, curcumin inhibits TPA-induced skin tumor promotion in mice. The mechanisms for the anticarcinogenic effects of curcumin are similar to those of the GTPs. Curcumin enhances glutathione content and glutathione-S-transferase activity in liver; and it inhibits lipid peroxidation and arachidonic acid metabolism in mouse skin, protein kinase C activity in TPA-treated NIH 3T3 cells, chemically induced ODC and tyrosine protein kinase activities in rat colon, and 8-hydroxyguanosine formation in mouse fibroblasts. Ellagic acid is a polyphenol found abundantly in various fruits, nuts and vegetables. Ellagic acid is active in antimutagenesis assays, and has been shown to inhibit chemically induced cancer in the lung, liver, skin and esophagus of rodents, and TPA-induced tumor promotion in mouse skin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Polyphenols as cancer chemopreventive agents. 853 95


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