Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activity of a group of respiratory enzymes was studied in normal menopausal as well as benign and malignant tumours. A decrease in the activity of succinic dehydrogenase, diphosphopyridine nucleotide diaphorase and cytochrome oxidase in malignant tumours especially in spindle cell sarcoma and undifferentiated adenocarcinoma was observed. Benign tumours manifested variable results, thus cellular fibromyoma showed no changes in the activity of succinic dehydrogenase, diphosphopyridine nucleotide diaphorase and cytochrome oxidase whereas fibromyomal cells exhibited less enzymatic activity. In addition, no marked difference was observed in the activity of glucose-6-phosphate dehydrogenase in the aforementioned tumours as compared with normal menopausal uterine tissues.
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PMID:Cytoenzymology of benign and malignant tumours of the corpus uteri. I. Respiratory enzymes. 18 37

The indoloquinone EO9 exhibits promising in vitro and in vivo antitumour activity. EO9 is metabolised to DNA damaging species by DT-diaphorase in vitro. In the present study DT-diaphorase specific activity was 16 fold higher in the mouse adenocarcinoma MAC 16, a tumour which is quite responsive to EO9 in vivo, compared with levels in the more resistant mouse adenocarcinoma MAC 26. This order of responsiveness is the reverse of that seen with the most active of the clinically used agents in these tumours [chloroethylnitrosoureas and 5-fluorouracil (5-FU)]. In addition, when the in vitro sensitivity of two human colon carcinoma cell lines was compared, EO9 was 15-30 fold more active in the DT-diaphorase rich HT29 line than in the enzyme-deficient BE cell line counterpart. These results are consistent with the hypothesis that DT-diaphorase expression may be a major determinant of the sensitivity of tumours to EO9. This should be considered in the clinical development of the drug.
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PMID:DT-diaphorase activity correlates with sensitivity to the indoloquinone EO9 in mouse and human colon carcinomas. 138 72

In the present study, we investigated Phase I (cytochrome P450; DT-diaphorase, DTD) and Phase II (epoxide hydrolase, EH; glutathione-S-transferases, GSTs) enzymes in normal colon from patients without colorectal adenocarcinoma and in peritumoral and tumoral tissues from patients with colorectal adenocarcinoma. No significant changes in levels of cytochrome P450IIIA4 (the only P450 detectable in this tissue), EH, GSTs and DTD activity were found between normal and peritumoral tissues. In tumoral tissue, compared with peritumoral tissues, we observed significant decreases in cytochrome P450IIIA4 (-50%, P less than 0.002) and EH (-60%, P less than 0.03), no change in DTD activity and significant increases in GST pi (+40%, P less than 0.03) and total GST activity (+30%, P less than 0.01). The numerous changes observed in tumoral tissues suggest that variations in drug-metabolizing enzyme expression in colorectal adenomatous polyps could represent pretumoral markers. Moreover, a better understanding of the expression of these enzymes in tumoral tissues would help us to choose the most appropriate colon tumor cell lines for the testing of new anti-cancer drugs.
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PMID:Drug-metabolizing enzyme expression in human normal, peritumoral and tumoral colorectal tissue samples. 202 56

A point mutation in the mRNA of NADP(H): quinone oxidoreductase 1 (NQO1, DT-diaphorase) is believed to be responsible for reduced enzyme activity in the adenocarcinoma BE cell line. The present study examined nine cultured human non-cancerous fibroblast cell strains, five of which were from members of a single cancer-prone family, which demonstrated widely varying activity levels of DT-diaphorase (41 - 3462 nmol min-1 mg-1 protein), to determine if genetic alteration of the NQO1 or NOQ2 gene was involved in determining enzyme activity. All cell strains expressed NQO1 and NQO2 mRNA as measured by a quantitative polymerase chain reaction amplification technique. No relationship was found between the level of mRNA expressed and the enzyme activity in the cells. Sequencing of the entire complementary DNA from the cell strains revealed only a single base substitution at nucleotide 609 in one allele encoding NQO1 in every cell strain from members of the cancer-prone family, except for one cell strain which expressed only the T at nucleotide 609 in both alleles. Subsequent examination of genomic DNA from 44 individuals revealed that this base substitution is present in approximately 50% of the population. The presence of the T at nucleotide 609 in the NQO1 locus does not appear to be directly causal for altered DT-diaphorase activity.
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PMID:Presence of a heterozygous substitution and its relationship to DT-diaphorase activity. 766 61

High-level cytosolic class-3 aldehyde dehydrogenase (ALDH-3)-mediated oxazaphosphorine-specific resistance (> 35-fold as judged by the concentrations of mafosfamide required to effect a 90% cell-kill) was induced in cultured human breast adenocarcinoma MCF-7/0 cells by growing them in the presence of 30 microM catechol for 5 days. Resistance was transient in that cellular sensitivity to mafosfamide was fully restored after only a few days when the inducing agent was removed from the culture medium. The operative enzyme was identified as a type-1 ALDH-3. Cellular levels of glutathione S-transferase and DT-diaphorase activities, but not of cytochrome P450 IA1 activity, were also elevated. Other phenolic antioxidants, e.g. hydroquinone and 2,6-di-tert-butyl-4-hydroxytoluene, also induced ALDH-3 activity when MCF-7/0 cells were cultured in their presence. Thus, the increased expression of a type-1 ALDH-3 and the other enzymes induced by these agents was most probably the result of transcriptional activation of the relevant genes via antioxidant responsive elements present in their 5'-flanking regions. Cellular levels of ALDH-3 activity were also increased when a number of other human tumor cell lines, e.g. breast adenocarcinoma MDA-MB-231, breast carcinoma T-47D and colon carcinoma HCT 116b, were cultured in the presence of catechol. These findings should be viewed as greatly expanding the number of recognized environmental and dietary agents that can potentially negatively influence the sensitivity of tumor cells to cyclophosphamide and other oxazaphosphorines.
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PMID:Phenolic antioxidant-induced overexpression of class-3 aldehyde dehydrogenase and oxazaphosphorine-specific resistance. 788 82

A series of analogues of the novel hypoxia-selective cytotoxin 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide (6) have been prepared and evaluated, in a search for compounds which retain high hypoxic selectivity but have increased potency and/or aqueous solubility. Several analogues with ionizable or dipolar carboxamide side chains showed improved solubility but generally had reduced cytotoxic potency and hypoxic selectivity. Modification of the mustard leaving groups or replacement of the carboxamide moiety provided some compounds with superior potency, but only the mixed chloro/mesylate mustard 20 provided a gain in potency relative to solubility while retaining the hypoxic selectivity of 6. These nitrogen mustards did not show the remarkable activity demonstrated by the related aziridine 7 [CB 1954, 5-(N-aziridinyl)- 2,4-dinitrobenzamide] in Walker 256 adenocarcinoma cells and are not efficient substrates for the DT-diaphorase which activates the latter compound by aerobic nitroreduction in Walker cells. Variations in hypoxic selectivity within the dinitrobenzamide mustards appear not to be due to differences in sensitivity to activation by this enzyme. Walker cells showed intermediate sensitivity to the mono(2-chloroethyl) analogue 26 but not to the related half-mustard 27, suggesting that the inhibition of DT-diaphorase activity is due to steric effects in the 5-position. The preferred compound overall with respect to solubility, potency, and in vitro hypoxic cell selectivity was the (dimethylamino)-ethyl derivative 11. DNA elution studies and comparison of the sensitivity of AA8 and UV4 cells to this compound indicated reductive activation to form a DNA cross-linking agent under hypoxia. Radiobiological studies indicated 11 to be equally active against both aerobic and hypoxic cells in KHT tumors. It is not clear whether this reflects efficient killing of aerobic cells as a result of diffusion of reduced metabolites from hypoxic regions or whether cytotoxicity in tumors is independent of hypoxia.
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PMID:Hypoxia-selective antitumor agents. 9. Structure-activity relationships for hypoxia-selective cytotoxicity among analogues of 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide. 803 24

The class-3 aldehyde dehydrogenase that is overexpressed (> 100-fold) in human breast adenocarcinoma MCF-7/0 cells made resistant (> 30-fold as judged by LC90s) to oxazaphosphorines, such as mafosfamide, by growing them in the presence of polycyclic aromatic hydrocarbons, e.g., methylcholanthrene (3 microM for 5 days), was isolated and characterized. Its physical and catalytic properties were identical to those of the prototypical human stomach mucosa cytosolic class-3 aldehyde dehydrogenase, type-1 ALDH-3, except that it catalyzed, though not very rapidly, the oxidation of aldophosphamide, whereas the stomach mucosa enzyme essentially did not; hence, it was judged to be a slight variant of the prototypical enzyme. Carcinogens that are not ligands for the Ah receptor, barbiturates known to induce hepatic cytochrome P450s, steroid hormones, an antiestrogen, and oxazaphosphorines did not induce the enzyme or the largely oxazaphosphorine-specific acquired resistance. Whereas methylcholanthrene induced (a) resistance to mafosfamide and (b) class-3 aldehyde dehydrogenase activity, as well as glutathione S-transferase and DT-diaphorase activities, in the estrogen receptor-positive MCF-7/0 cells, it did not do so in two other human breast adenocarcinoma cell lines, MDA-MB-231 and SK-BR-3, each of which is estrogen receptor negative. Expression of the class-3 aldehyde dehydrogenase and the loss of sensitivity to mafosfamide by polycyclic aromatic hydrocarbon-treated MCF-7/0 cells were transient; each returned to essentially basal levels within 15 days when the polycyclic aromatic hydrocarbon was removed from the culture medium. Insensitivity to the oxazaphosphorines on the part of polycyclic aromatic hydrocarbon-treated MCF-7/0 cells was not observed when exposure to mafosfamide (30 min) was in the presence of benzaldehyde or octanal, each a relatively good substrate for cytosolic class-3 aldehyde dehydrogenases, whereas it was retained when exposure to mafosfamide was in the presence of acetaldehyde, a relatively poor substrate for these enzymes. These observations demonstrate that ligands for the Ah receptor can induce a transient, largely oxazaphosphorine-specific, acquired cellular resistance, and they are consistent with the notion that elevated levels of a cytosolic class-3 aldehyde dehydrogenase nearly identical to the prototypical type-1 class-3 aldehyde dehydrogenase expressed by human stomach mucosa account for the Ah receptor ligand-induced oxazaphosphorine-specific acquired resistance, most probably by catalyzing the detoxification of aldophosphamide.
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PMID:Identification of a methylcholanthrene-induced aldehyde dehydrogenase in a human breast adenocarcinoma cell line exhibiting oxazaphosphorine-specific acquired resistance. 817 25

To study the regulation of the human detoxicating enzyme DT diaphorase (DTD) under hypoxic conditions, we examined the effects of heat and hypoxia, and their interaction, on the steady-state levels of mRNA and DTD enzyme activity in human colon adenocarcinoma HT29 cells. We found that a 1-h heat treatment (42.5 degrees C) markedly increased the specific activity of DTD. Elevated enzyme activity was observed within 30 min, peaked at 6 h, and had almost returned to baseline by 36 h. The effect of hypoxia alone on DTD enzyme activity developed more slowly, with a maximal response at 24 h, and return to baseline at 72 h. The effect of a 1-h heat treatment was not inhibited by subsequent hypoxic exposure for 8 h. The effect of hypoxia was also not inhibited by heat in any schedule. However, a 1-h exposure to heat during 8 h hypoxic exposure induced the transcriptional effects of heat treatment much earlier. Heat shock followed by hypoxic stress resulted in prolonged elevation of DTD activity similar to that observed with hypoxia alone. We found that DTD mRNA content was elevated with a time course concordant with that of the enzyme activity. These data suggest that hypoxia and heat shock induce expression of the DTD gene independently. The mechanism of heat effect on DTD gene expression was investigated. Gel retardation assays demonstrated the induction of a binding activity of heat-induced transcription factor(s) to heat shock elements following both heat and hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction of heat and hypoxia in modulating transcription of DT diaphorase in human colon adenocarcinoma cells. 818 Jan 25

The expression of intrinsic resistance to cisplatin in two lung cancer cell lines, one derived from a small cell carcinoma (SW1271) and the other from an adenocarcinoma (A549), relative to a drug-sensitive small cell line SW900, was characterized by: (i) expression of cross-resistance to mitomycin C and cadmium chloride, but increased sensitivity to adriamycin and etoposide; (ii) significantly decreased cisplatin uptake; (iii) elevated levels of glutathione which could be reduced by buthionine L-sulfoximine resulting in significant sensitization of the cells to cisplatin; (iv) a lack of consistent modification of metallothionein content and expression of levels of glutathione S-transferase, glutathione reductase and glutathione peroxidase or of activities of DT-diaphorase or catalase; (v) significantly reduced total DNA-platination levels immediately following a 1 h cisplatin treatment with 10 micrograms/ml (33.3 microM); (vi) increased removal of Pt-GG and Pt-AG adducts by the A549 cells, consistent with increased repair capacity, but a lack of removal of these major adducts by the SW1271 cells indicative of tolerance of this drug-induced DNA damage. These data therefore provide evidence of differential formation, repair and tolerance of DNA damage following exposure of three human lung carcinoma cell lines to cisplatin.
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PMID:Evidence of differential cisplatin-DNA adduct formation, removal and tolerance of DNA damage in three human lung carcinoma cell lines. 840 Mar 52

DT-diaphorase (DTD) activity has been related to bioactivation and cytotoxicity of antitumor quinones. A pair of human colon adenocarcinoma cell lines, HT29 and BE, were used in this study to examine the role of DTD in antitumor quinone induced apoptosis. HT29 cells have elevated levels of DTD whereas BE cells lack functional DTD due to a point mutation which results in a complete lack of DTD activity. MeDZQ, a quinone that is efficiently bioactivated by DTD, induced apoptosis both in HT29 and BE cells, but with a much higher incidence in HT29, as assessed by morphological criteria and the formation of oligonucleosomal fragments of DNA. Two other quinone compounds which are also substrates for DTD, i.e. streptonigrin and mitomycin C, also preferentially induced apoptosis in HT29 cells, which could be inhibited by dicoumarol. Our data suggest that bioreductive activation of antitumor quinones by DTD results in induction of apoptosis in human colon carcinoma cells.
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PMID:Quinone-induced apoptosis in human colon adenocarcinoma cells via DT-diaphorase mediated bioactivation. 865 8


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