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)

Mitomycin C (MMC), an alkylating anti-tumor agent, was activated by non-enzymatic and enzymatic mechanisms leading to DNA binding and adduct formation. However, it was enzymatically, not non-enzymatically, activated MMC which induced inter-strand DNA cross-linking, a major determinant of cell death. The enzymatic activation of MMC was catalyzed by microsomal NADPH:cytochrome P450 reductase (P450 reductase) and cytosolic enzyme activities. Human P450 reductase, transiently expressed from its cDNA in the COSI cells, metabolically activated MMC to generate 9 specific MMC-DNA adducts and induced inter-strand DNA cross-linking. Co-chromatography of the MMC-DNA adducts generated by P450 reductase and sodium borohydride in separate experiments indicated that MMC was metabolized by P450 reductase to produce 2,7-diaminomitosenes that exhibited binding to deoxyguanosine. Several experiments indicated that cytosolic enzymes which catalyzed reductive activation of MMC and DNA cross-linking included NAD(P)H:quinone oxidoreductaseI (NQOI or DT diaphorase) when present in extremely high concentrations and a unique cytosolic activity. The unique cytosolic activity was present in several mammalian cells and mouse colon and liver but absent in mouse kidney. The unique activity had properties of a diaphorase but was distinct from NQOI because of a lack of correlation between NQOI (2,6-dichlorophenolindophenol reduction) activity and the amount of MMC-reductive activation leading to DNA cross-linking. This activity was also distinct from xanthine oxidoreductase and NADH-cytochrome b5 reductase, 2 other enzymes that catalyze metabolic activation of MMC, because the unique activity was not inhibited by allopurinol (an inhibitor of xanthine oxidoreductase) and its activity was the same with NADH and NADPH (cytochrome b5 reductase is specific to NADH).
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PMID:Non-enzymatic and enzymatic activation of mitomycin C: identification of a unique cytosolic activity. 856 27

We studied a selective enhancement of the mitomycin C (MMC)-induced antitumor effect focusing on the intracellular metabolism by NAD(P)H:quinone oxidoreductase (DT-diaphorase, DTD). The level of cellular DTD activity related well to the degree of MMC-induced DNA total cross links and cell growth inhibition in human cancer cell lines, KB, PH101, SH101 and K562. A DTD inhibitor, dicoumarol (DIC) or flavin adenine dinucleotide (FAD), inhibited the MMC-induced DNA damage and cytotoxicity at a non-toxic concentration. The DTD-mediated MMC activation was pH-dependent, and highest at pH 6 and lowest at pH 8. Although an inverse relationship appeared to exist between DTD activity and MMC efficacy in human xenografts implanted into nude mice and 9 fresh human tumor specimens, the investigation in 3 culture cells, HEC-46, HCC-48 and HCC-50, established from those xenografts, showed that DTD activated MMC in a pH-dependent manner as well as the other cell lines. Significant tumor pH reduction from 7.1 to 6.7 by continuous glucose infusion also increased the MMC-induced tumor growth inhibition in the human tumor xenografts. Thus, we conclude that bioreductive activation by DTD in a pH-dependent manner may be of key importance in the MMC-induced antitumor effect and that an increased MMC efficacy at a reduced pH caused by hyperglycemia may be applied to clinical use as a new manipulation for a biochemical modulation of MMC.
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PMID:DT-diaphorase as a target enzyme for biochemical modulation of mitomycin C. 856 14

In the present study, we investigated the effects of high levels of dietary fish oil on the growth of MX-1 human mammary carcinoma and its response to mitomycin C (MC) treatment in athymic mice. We found that high levels of dietary fish oil (20% menhaden oil + 5% corn oil, w/w) compared to a control diet (5% corn oil, w/w) not only lowered the tumor growth rate, but also increased the tumor response to MC treatment. We also found that high levels of dietary fish oil significantly increased the activities of tumor xanthine oxidase and DT-diaphorase, which are proposed to be involved in the bioreductive activation of MC. Since menhaden oil is highly unsaturated, its intake caused a significant increase in the degree of fatty acid unsaturation in tumor membrane phospholipids. This alteration in tumor membrane phospholipids made the tumor more susceptible to oxidative stress, as indicated by the increased levels of both endogenous lipid peroxidation and protein oxidation after feeding the host animals the menhaden oil diet. In addition, the tumor antioxidant enzyme activities, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPOx), and glutathione S-transferase peroxidase (GSTPx), were all significantly enhanced by feeding a diet high in fish oil. MC treatment caused further increases in tumor lipid peroxidation and protein oxidation, as well as in the activities of CAT, SOD, GPOx, and GSTPx, suggesting that MC causes oxidative stress in this tumor model which is exacerbated by feeding a diet high in menhaden oil. Thus, feeding a diet rich in menhaden oil decreased the growth of human mammary carcinoma MX-1, increased its responsiveness to MC, and increased its susceptibility to endogenous and MC-induced oxidative stress, and increased the tumor activities of two enzymes proposed to be involved in the bioactivation of MC, that is, DT-diaphorase and xanthine oxidase. These findings support a role of these two enzymes in the bioactivating of MC and indicate that the type of dietary fat may be important in tumor response to therapy.
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PMID:Dietary menhaden oil enhances mitomycin C antitumor activity toward human mammary carcinoma MX-1. 856 32

Inducibility of oxidative stress by menadione-associated redox cycling activation under redox-enzyme modulated conditions was examined in F344 male rat liver, by monitoring 8-hydroxydeoxyguanosine (8-OHdG) levels in DNA and hepatocyte injury. Further, the treatment-associated liver tumor-initiating, -promoting and -progressing potentials were assessed in terms of development of enzyme-altered preneoplastic foci, neoplastic nodules and hepatocellular carcinomas. With or without menadione, redox-enzyme modulation consisting of increased cytochrome P450 reductase by phenobarbital (PB), depletion of glutathione by phorone, inhibition of DT-diaphorase by dicumarol, with or without further supplement of iron, caused both 8-OHdG production and hepatocyte necrosis. Thus-induced oxidative stress exerted liver tumor promoting-activity in N-nitrosodiethylamine (DENA)-initiated rats, but neither initiating activity when promoted by 0.05% PB diet for 64 weeks, nor progressing activity when the oxidative stress was given for 33 weeks to preneoplastic nodule-bearing rats which was induced by DENA.
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PMID:Effects of oxidative stress induced by redox-enzyme modulation on rat hepatocarcinogenesis. 859 86

The two-electron bioreductive enzyme DT-diaphorase catalyzes the metabolism of quinones. The existence of several distinct sizes of DT-diaphorase mRNA transcripts has been observed in human tissues. One of these, an alternatively spliced mRNA that lacks exon 4, has been recently found to be expressed at levels comparable to those of the full-length mRNA. The protein encoded by the mRNA lacking exon 4 has minimal catalytic activity, consistent with the elimination of the quinone-binding site coded for by this exon. We have pursued a number of approaches to examine the significance of this splice variant. We identified a similar truncated transcript in a human HepG2 cDNA library. To determine the frequency of expression of this form of DT-diaphorase in the general population, we examined mRNA obtained from the peripheral mononuclear cells of 16 patients and found substantial interindividual variability in the patterns of transcript expression. Following treatment of these 16 patients with 20 mg/m2 mitomycin C (MMC), the induction of DT-diaphorase transcripts was demonstrated. In most patients, expression of the variant transcript (lacking exon 4) remained constant, while that of the full-length mRNA was elevated. The extent of induction also showed interindividual variability. In one patient, while both transcripts were present at baseline, expression of the variant transcript disappeared almost completely after MMC treatment. To analyze these events under more controlled conditions, we examined the effects of MMC treatment on two human colon tumor cell lines. MMC treatment induced expression of the full-length mRNA but did not influence the abundance of the variant transcript. We then performed single-strand conformational polymorphism analysis of genomic DNA from the 16 patients to investigate the potential role of cis-acting factors in the variable splicing responses. Two patients demonstrated sequence differences in the region spanning exon 4, but in neither was the change in a region critical to splicing regulation. These data demonstrate that the expression of DT-diaphorase in hyman cells is polymorphic, and that the levels of individual transcripts can be regulated by exogenous factors. The findings support a role for alternative splicing in the control of DT-diaphorase gene expression.
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PMID:Alternative splicing and differential expression of DT-diaphorase transcripts in human colon tumors and in peripheral mononuclear cells in response to mitomycin C treatment. 862 Apr 84

2,3,5-Trimethyl-6-(3-pyridylmethyl)1,4-benzoquinone (CV-6504), an inhibitor of 5-lipoxygenase and thromboxane A2 synthase and a scavenger of active oxygen species, has been shown to exhibit profound anti-tumour activity against three established murine adenocarcinomas (MACs) that are generally refractory to standard cytotoxic agents. For the cachexia-inducing MAC16 tumour, optimal anti-tumour activity was seen at dose levels of 10 and 25 mg kg-1 day-1, together with a reversal of cachexia and a doubling of the time to sacrifice of the animals through cachexia from 8 days to 17 days. The remaining tumour fragments showed extensive necrosis in regions distal from the blood supply. Growth of the MAC13 tumour was also effectively suppressed at dose levels between 5 and 50 mg kg-1 day-1, resulting in a specific growth delay between 1.0 and 1.2. Growth of the MAC26 tumour was also inhibited a concentration-related manner, with doses of 25-50 mg kg-1 day-1 being optimal. Anti-tumour activity towards all three tumours at low dose levels of CV-6504 was effectively suppressed by concurrent administration of linoleic acid (1 g kg-1 day-1), suggesting that inhibition of linoleate metabolism was responsible for the anti-tumour effect. Tumour sensitivity may be correlated with increased DT-diaphorase that are required to metabolise CV-6504 to the active hydroquinone, which inhibits 5-lipoxygenase activity.
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PMID:Novel anti-tumour activity of 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4- benzoquinone (CV-6504) against established murine adenocarcinomas (MAC). 863 Feb 77

Mitomycin C (MMC), a known cytotoxic agent, requires cellular enzyme-mediated activation for effective antitumor activity. To study the bioreductive enzymes responsible for MMC activation in tumor cells, we examined the enzyme activities of DT-diaphorase (DTD) and NADPH:cytochrome P-450 reductase in 13 colon and gastric carcinoma cell lines and then compared these activities to the respective cellular MMC sensitivity. We found that cell lines with nonexistent or marginal DTD activity, such as St-4 and MKN7, showed resistance to MMC, in comparison to cell lines with DTD activity ranging from 210 to 1420 nmol/min/mg protein. No correlation was found between NADPH:cytochrome P-450 reductase activity and MMC sensitivity in these cell lines. To confirm the role of DTD in cellular MMC sensitivity, we constructed an expression vector containing NQO1, a gene that codes for DTD, and transfected the vector into St-4 cells expressing no DTD activity. Several transfectant clones with DTD activity from 144 to 2085 nmol/min/mg protein were obtained. All of the transfectants showed 5-10-fold higher sensitivity to MMC compared to the parental St-4 cells. Consistent with the MMC sensitivity, we also found that MMC-DNA adduct was formed more extensively in the NQO1 transfectants than in the St-4 cells. These results indicate that DTD activity is required for effective cytotoxicity of MMC in colon and gastric carcinoma cells.
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PMID:DT-diaphorase as a critical determinant of sensitivity to mitomycin C in human colon and gastric carcinoma cell lines. 866 20

Fruit extracts of four Vaccinium species (lowbush blueberry, bilberry, cranberry, and lingonberry) were screened for anticarcinogenic compounds by a combination of fractionation and in vitro testing of their ability to induce the Phase II xenobiotic detoxification enzyme quinone reductase (QR) and to inhibit the induction of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis, by the tumor promoter phorbol 12-myristate 13-acetate (TPA). The crude extracts, anthocyanin and proanthocyanidin fractions were not highly active in QR induction whereas the ethyl acetate extracts were active QR inducers. The concentrations required to double QR activity (designated CDqr) for the ethyl acetate extracts of lowbush blueberry, cranberry, lingonberry, and bilberry were 4.2, 3.7, 1.3, and 1.0 microgram tannic acid equivalents (TAE), respectively, Further fractionation of the bilberry ethyl acetate extract revealed that the majority of inducer potency was contained in a hexane/chloroform subfraction (CDqr = 0.07 microgram TAE). In contrast to their effects on QR, crude extracts of lowbush blueberry, cranberry, and lingonberry were active inhibitors of ODC activity. The concentrations of these crude extracts needed to inhibit ODC activity by 50% (designated IC50) were 8.0, 7.0, and 9.0 micrograms TAE, respectively. The greatest activity in these extracts appeared to be contained in the polymeric proanthocyanidin fractions of the lowbush blueberry, cranberry, and lingonberry fruits (IC50 = 3.0, 6.0, and 5.0 micrograms TAE, respectively). The anthocyanidin and ethyl acetate extracts of the four Vaccinium species were either inactive or relatively weak inhibitors of ODC activity. Thus, components of the hexane/chloroform fraction of bilberry and of the proanthocyanidin fraction of lowbush blueberry, cranberry, and lingonberry exhibit potential anticarcinogenic activity as evaluated by in vitro screening tests.
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PMID:In vitro anticancer activity of fruit extracts from Vaccinium species. 869 31

Aziridinylbenzoquinones are a group of antitumor agents that elicit cytotoxicity by generating either alkylating intermediates or reactive oxygen species. The mechanism of toxicity may not always, however, involve profound damage of cellular constituents, but may involve a cytostatic effect through interference with the cell cycle. In this context, we have examined the induction of the cell cycle inhibitor p21 (WAF1, CIP1, or sdi1), whose overexpression suppresses the growth of various tumor cells, in human tumor cells metabolizing 3,6-diaziridinyl-1,4-benzoquinone (DZQ) and its C2,C5-substituted derivatives: 2,5-bis-(carboethoxyamino) (AZQ) and 2, 5-bis-2(-hydroxyethylamino) (BZQ). Both DZQ and AZQ were effectively activated by HCT116 human colonic carcinoma cells; the activation of the former involved largely a dicoumarol-sensitive activity, whereas that of the latter appeared to be accomplished primarily by one-electron transfer reductases. BZQ was not a substrate for the dicoumarol-sensitive enzyme in HCT116 cells. Cellular activation of the first two quinones was associated with formation of oxygen-centered radicals as detected by EPR in conjunction with the spin trap 5,5'-dimethyl-1-pyrroline-N-oxide. The redox transitions of DZQ involved hydroxyl radical formation and were strongly inhibited by catalase, whereas those of AZQ showed a strong superoxide anion component sensitive to superoxide dismutase. These signals were suppressed by N-acetylcysteine with concomitant production of a thiyl radical adduct. This suggests an effective electron transfer between the thiol and free radicals formed during the activation of these quinones. DZQ and AZQ induced significantly the expression of p21 in HCT116 cells, but a 10-fold higher concentration of AZQ was required to achieve the level of induction elicited by DZQ. BZQ had little effect on p21 expression. p21 induction at both mRNA and protein levels correlated with the inhibition of either cyclin-dependent kinase activity or cell proliferation. p21 induction elicited by the above quinones was inhibited by N-acetylcysteine, whereas the non-sulfur analog, N-acetylalanine, was without effect. Catalase and superoxide dismutase did not effect p21 induction by aziridinylbenzoquinones in HCT116 cells, thus suggesting that extracellular sources of oxygen radicals generated by plasma membrane reductases have no influence in the expression of this gene. Hydrogen peroxide, a product of quinone redox cycling, elicited an increase of p21 mRNA levels in HCT116 and K562 human chronic myelogenous leukemia cells. The latter lacks p53, one of the activators of p21 transcription, thus suggesting that p21 expression can be accomplished in a p53-independent manner in these cells. This study suggests that p21 induction is mediated by an increase in the cellular steady-state concentration of oxygen radicals and that the greater effectiveness in p21 induction by DZQ may be related to its efficient metabolism by NAD(P)H:quinone oxidoreductase activity in HCT116 cells.
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PMID:Induction of p21 mediated by reactive oxygen species formed during the metabolism of aziridinylbenzoquinones by HCT116 cells. 894 36

Genes involved in the metabolic activation or detoxification of environmental carcinogens may contribute to breast cancer susceptibility by influencing rates of somatic mutation. To examine this hypothesis, we studied the association between loss of constitutional heterozygosity (LOH) in ductal breast tumors and allelic variability in genes that regulate the metabolism of environmental carcinogens. LOH was measured by typing the tumor and normal tissue of 28 breast cancer cases at 33 chromosomal loci by using highly polymorphic tetranucleotide repeat markers. Genotypes in non-tumor tissue were also measured at the cytochrome P450 1A1 (CYP1A1), cytochrome P450 2D6 (CYP2D6), glutathione-s-transferase mu (GSTM), epoxide hydrolase (EH), and NAD(P)H:quinone oxidoreductase (NQO1) loci. The observed proportion of LOH was 11% overall and ranged from 0% to 37% across loci. LOH greater than 20% was observed on chromosomes 1p, 2p, 10q, 11q, 17p, and 18q. The observed proportion of LOH ranged from 0% to 67% among individuals. An elevated proportion of LOH was observed for genotypes at CYP2D6 (17% for the 1/1 and 1/2 genotypes vs 8% for the 2/ 2 genotype), NQO1 (13% for the 1/2 and 2/2 genotypes vs 8% for the 1/1 genotype), and GSTM (15% for the null genotype vs 7% for the wild-type genotype). No elevated proportion of LOH was observed for genotypes at CYP1A1 (12% for the 1/2 genotype vs 10% for the 1/1 genotype) or EH (11% for the 1/1 genotype vs 10% for the 1/2 genotype). There was no correlation of LOH with any other tumor characteristic such as estrogen- or progesterone-receptor status or number of positive lymph nodes. These results suggest that the proportion of LOH varies substantially across loci and among individuals. Interindividual variability in LOH may thus be explained in part by genes that regulate the metabolism of environmental carcinogens.
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PMID:Variability in loss of constitutional heterozygosity across loci and among individuals: association with candidate genes in ductal breast carcinoma. 894 71


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