Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.2 (NQO1)
 6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

RH1 (2,5-diaziridinyl-3-(hydroxylmethyl)-6-methyl-1,4-benzoquinone) has shown preferential activity against human tumour cell lines which express high levels of DTD (EC 1.6.99.2; NAD(P)H:quinone oxidoreductase, NQO1, DT-diaphorase) and is a candidate for clinical trials. EO9 (3-hydroxy-5-aziridinyl-1-methyl-2-[1H indole-4,7-dione]prop-beta-en-alpha-ol) is a known substrate for DTD but clinical trials were disappointing, as a result of rapid plasma clearance and reversible dose-limiting kidney toxicity. It is an obvious concern that RH1 does not exhibit the same limitations. We therefore describe the antitumour activity and pharmacology of RH1 in mice and compare its pharmacological characteristics to those of EO9. Significant antitumour activity (P = 0.01) was seen for RH1 (0.5 mg/kg, i.p.) against the high DTD-expressing H460 human lung carcinoma. Pharmacokinetic analysis of RH1 in mice showed a t1/2 of 23 min with an area under the curve of 43.0 ng hr mL(-1) resulting in a calculated clearance of 5.1 mL min(-1), 10-fold slower than EO9. RH1 was also more stable than EO9 in murine blood, where the breakdown was thought to be DTD-related. NADH-dependent microsomal metabolism of RH1 and EO9 in both liver and kidney was slow (<100 pmol/min/g tissue), reflecting the low microsomal DTD expression (<35 nmol/mg/min). Liver cytosol metabolism was rapid for both compounds (>4500 pmol/min/g tissue), although DTD levels were low (21.4+/-0.6 nmol/mg/min). DTD activity in the kidney cytosol was high (125+/-8.2 nmol/mg/min) and EO9 was rapidly metabolised (4396+/-1678 pmol/min/g), but the metabolic rate for RH1 was 7-fold slower (608+/-86 pmol/min/g), even though RH1 was shown to be an excellent substrate for DTD (Vmax = 800 micromol/min/mg and a Km of 11.8 microM). The two DTD substrates RH1 and EO9 are clearly metabolised differently, suggesting that RH1 may have different pharmacological properties to those of EO9 in the clinic.
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PMID:Pharmacological properties of a new aziridinylbenzoquinone, RH1 (2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone), in mice. 1071 41

Pivalyloxymethyl butyrate (AN9) is an anticancer derivative of butyric acid. In this study, doxorubicin (DXR) and AN9 synergistically inhibited the growth of lymphoma and lung carcinoma cells, whereas there was no synergy between AN9 and antimetabolites. AN9 did not affect the intracellular uptake of DXR. Among anthracyclines and their derivatives, the synergistic effect was prominent in compounds with a daunosamine moiety, suggesting that AN9 may affect the catabolism of these compounds. The degradation of DXR in the extract from AN9-treated cells was much less than that in extract from untreated cells. AN9 did not directly inhibit the enzyme activity but rather suppressed expression of the enzyme. With respect to the expression of drug resistance-related genes, there was no significant difference between untreated and AN9-treated cells. However, AN9 significantly down-regulated the levels NADPH-cytochrome P450 reductase and DT-diaphorase mRNA in the presence of DXR but not the level of xanthine oxidase mRNA. The enhancement of the sensitivity to anthracyclines was closely associated with the suppression of the mRNA expression.
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PMID:Anticancer derivative of butyric acid (Pivalyloxymethyl butyrate) specifically potentiates the cytotoxicity of doxorubicin and daunorubicin through the suppression of microsomal glycosidic activity. 1086 Sep 24

Genetic variations in metabolic activation or detoxification enzymes have been thought to contribute to individual differences in lung cancer susceptibility. Genetic polymorphisms of NAD(P)H quinone oxidoreductase (NQO1), cytochrome P4501A1 (CYP1A1) and microsomal epoxide hydrolase (HYL1) have been associated with increased lung cancer risk in Asian populations. In the present study, the possibility of an association of NQO1, CYP1A1 and HYL1 genetic polymorphisms with lung cancer was examined among residents in Nanjing, China. A total of 84 lung cancer patients and 84 control subjects were matched by age, gender, occupation and smoking status. No significant association was observed for these genetic polymorphisms with the overall incidence of lung cancer. When the groups were stratified according to smoking status, we found that smokers carrying the HYL1*2 allele had a higher relative risk for lung cancer Odds ratio ((OR), 5.66; 95% confidence interval (95% CI), 1.71-18.68). The association was also found with squamous cell carcinoma (OR, 3.23; 95% CI, 1.00-10.38). Our results suggest that HYL1*2 polymorphism might be a risk factor for smoking-associated lung cancer in China.
Lung Cancer
PMID:Genetic polymorphisms of NAD(P)H quinone oxidoreductase, CYP1A1 and microsomal epoxide hydrolase and lung cancer risk in Nanjing, China. 1155 8

NAD(P)H: quinone oxidoreductase (NQO1) protects the cell against cytotoxicity by reducing the concentration of free quinone available for single electron reduction. The NQO1 gene is polymorphic and the variant protein exhibits just 2% of the enzymatic activity of the wildtype protein. In this study, we investigated NQO1 genotype in relation to lung cancer risk in patients attending a Manchester bronchoscopy clinic. The cases were patients with a current, or history of, malignant tumour of the lung, trachea or bronchus. The control group were all other patients attending the clinic who had never been diagnosed with a tumour. DNA extraction from bronchial lavage or blood samples and genotyping was successfully carried out for 82 of the cases and 145 controls. Patients carrying at least one variant allele were found to have almost a 4-fold increased risk of developing small cell lung cancer (adjusted OR=3.80, 95% C.I. 1.19-12.1). No association between NQO1 genotypes and non-small cell lung cancer risk was found. Furthermore, the excess small cell lung cancer risk associated with non-wildtype NQO1 genotypes was only apparent in heavy smokers where there was a >10-fold increased risk (adjusted OR=12.5, 95% C.I. 2.1-75.5). These results suggest that the NQO1 protein may be involved in the detoxification of those carcinogens associated with the development of small cell lung cancer. Individuals with reduced enzyme activity, due to a polymorphism in this gene, may therefore have an increased risk of developing this disease.
Lung Cancer 2001 Nov
PMID:Polymorphisms in the NAD(P)H: quinone oxidoreductase gene and small cell lung cancer risk in a UK population. 1167 76

Lung adenocarcinoma has replaced squamous cell lung carcinoma as the most frequent histological subtype in lung cancers. However, genetic factors that affect cancer susceptibility are much less understood in adenocarcinoma than in squamous cell carcinoma. In this study, polymorphisms in five genes involved in the metabolism of carcinogens or in the repair of damaged DNA in lung cells, NQO1-Pro187Ser, GSTT1-positive/null, GSTM1-positive/null, CYP1A1-Ile462Val, and OGG1-Ser326Cys, were examined for association with lung adenocarcinoma risk in a case-control study of 198 patients and 152 control subjects. The NQO1 and GSTT1 polymorphisms were associated with lung adenocarcinoma risk with adjusted odds ratio of 2.15 for the NQO1-Pro/Pro genotype versus the Ser/Ser genotype and adjusted odds ratio of 1.61 for the GSTT1-null genotype versus the positive genotype, respectively. Furthermore, individuals with the combined genotype of NQO1-Pro/Pro and GSTT1-null showed greater risk compared with those of NQO1-Ser/Ser and GSTT1-positive. In contrast, significant association was not observed for the GSTM1, CYP1A1, and OGG1 polymorphisms with lung adenocarcinoma risk, although several studies have shown their implication in the risk for squamous cell lung carcinoma. The result indicates that the NQO1-Pro/Pro and GSTT1-null genotypes are risk factors for lung adenocarcinoma development, and that the genetic factors for susceptibility to adenocarcinoma are different from those to squamous cell carcinoma. The enhanced risk of the NQO1-Pro/Pro genotype combined with the GSTT1-null genotype was more evident in smokers than in nonsmokers. Therefore, carcinogens in tobacco smoke, which are activated by NQO1 and detoxified by GSTT1, could have a role in lung adenocarcinoma development.
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PMID:Contribution of the NQO1 and GSTT1 polymorphisms to lung adenocarcinoma susceptibility. 1216 26

We assessed the association of three genetic polymorphisms, NAD(P)H quinone oxidoreductase (NQO1), Glutathione-S-transferase P1 (GSTP1), and manganese superoxide dismutase (MnSOD), with lung cancer risk in 198 cases and 332 controls in Taiwan. Overall, NQO1 and MnSOD polymorphisms were not associated with an increased risk of lung cancer. Individuals carrying variant alleles of GSTP1 were at higher risk of squamous cell lung carcinoma (odds ratio, 1.63; 95% confidence interval, 0.96-2.74). When the groups were further stratified by smoking status following gender and histological type, the wild-type NQO1 was associated with lung adenocarcinoma among smokers but not among nonsmokers (odds ratio, 2.49; 95% confidence interval, 1.17-5.32). These results suggest that NQO1 plays a role in the development of cigarette smoking-associated lung adenocarcinoma. In addition, GSTP1 polymorphism was associated with the risk of squamous cell lung carcinoma in Taiwan.
Lung Cancer 2003 May
PMID:Analysis of NQO1, GSTP1, and MnSOD genetic polymorphisms on lung cancer risk in Taiwan. 1271 Nov 12

To determine whether the human (h) NQO1 (NAD(P)H: quinone oxidoreductase 1) gene contains DNA sequences that directly mediate its high and low expression in non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC), respectively, a series of deletion constructs spanning up to -4kb of the 5(') flanking region of hNQO1 was used in transient transfection assays. The antioxidant response element (ARE) was found to be critical to the elevated expression of NQO1 in NSCLC. However, the ability of both heterologous and deletion promoter constructs to confer ARE responsiveness demonstrated that SCLC contains the necessary program/menu of transcription factors responsible to drive hNQO1 expression via the ARE. By examining the regulatory region of the hNQO1 gene, we identified a proximal repressor region between -259 and -131. These results provide the first evidence of a proximal repressor region exerting a negative role on the regulation of the hNQO1 promoter in SCLC.
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PMID:Differential expression of the antioxidant response element within the hNQO1 promoter in NSCLC versus SCLC. 1459 34

DT-diaphorase (DTD) is an obligate two-electron reductase which bioactivates chemotherapeutic quinones. DTD levels are elevated in a number of tumour types, including non-small cell lung carcinoma, colorectal carcinoma, liver cancers and breast carcinomas, when compared to the surrounding normal tissue. The differential in DTD between tumour and normal tissue should allow targeted activation of chemotherapeutic quinones in the tumour whilst minimising normal tissue toxicity. The prototypical bioreductive drug is Mitomycin C (MMC) which is widely used in clinical practice. However, MMC is actually a relatively poor substrate for DTD and its metabolism is pH-dependent. Other bioreductive drugs have failed because of poor solubility and inability to surpass other agents in use. RH1, a novel diaziridinylbenzoquinone, is a more efficient substrate for DTD. It has been demonstrated to have anti-tumour effects both in vitro and in vivo and demonstrates a relationship between DTD expression levels and drug response. RH1 has recently entered a phase I clinical trial in solid tumours under the auspices of Cancer Research UK. Recent work has demonstrated that DTD is present in the nucleus and is associated with both p53 and the heat shock protein, HSP-70. Furthermore, DTD is inducible by several non-toxic compounds and therefore much interest has focussed on increasing the differential in DTD levels between tumour and normal tissues.
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PMID:DT-diaphorase: a target for new anticancer drugs. 1524 76

The genetic susceptibility hypothesis has been used to explain why only a minority of smokers develop lung cancer. Only few studies have studied the role of polymorphisms in phase-I and II metabolizing genes, among young lung cancer patients. We have pooled the individual data of three studies from Denmark and Norway, including 320 patients diagnosed with non-small cell lung cancer at age 59 or below, and 618 age and gender matched controls. A questionnaire was used to determine relevant demographic and lifestyle characteristics, and polymorphisms in following genotypes were determined GSTM1, GSTM3, GSTP1, GSTT1, GPX1, MPO, NQO1 and NAT2. Based on the literature, the alleles of the genotypes were categorised as high- or low-risk alleles. No individual effect of the genotypes was found on the risk of lung cancer. Given a smoking exposure, the presence of high-risk alleles (or phenotypes) was generally found to increase the risk of lung cancer, although the effect modification did not reach statistical significance. A pattern of stronger protective effect was observed in carriers of more than one allele associated with lower risk of lung cancer, and a higher risk of lung cancer in carriers of one or more alleles associated with higher risk of lung cancer, but the results did not reach statistical significance. The effect modification was generally strongest at lower levels of smoking.
Lung Cancer 2005 May
PMID:Polymorphisms in genes involved in xenobiotic metabolism and lung cancer risk under the age of 60 years. A pooled study of lung cancer patients in Denmark and Norway. 1582 18


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