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)

NADPH-cytochrome P-450 reductase was purified to homogeneity from hepatoma 5123t.c.(H) microsomes from phenobarbital and hydrocortisone-treated rats by detergent solubilization and affinity chromatography with an overall 8% recovery. The purified enzyme has a minimum subunit molecular weight of 79 000 and contains one molecule each of FMN and FAD per 79 000 molecular weight. The purified hepatoma cytochrome P-450 reductase catalyzes electron transfer to artificial electron acceptors with Km values similar to those of purified liver reductase. The Km value of the hepatoma reductase for NADPH, 13 microM, is also similar to that of purified liver reductase. The tumor reductase appears immunochemically identical to liver reductase by Ouchterlony double-diffusion analysis and inhibition of activity. Peptide maps of the hepatoma and hepatic enzymes after proteolysis demonstrate the identity of the two proteins.
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PMID:Preparation of homogeneous NADPH-cytochrome P-450 reductase from rat hepatoma. 681 99

Pharmacokinetics of MMC was studied by bioassay method in cancer patients and experimental animals, and they were compared with those of a new mitomycin derivative, KW-2083. The blood level of MMC decreased relative by rapidly, t 1/2 beta in iv dose of 30, 20 and 10 mg/body to man was 50, 41 and 33 minutes, respectively. The drug level was able to increase locally by employing perfusion, arterial infusion, hemi-upper body infusion and intra-cavitary injection. The tissue level of MMC was high in the lung, kidney, muscle and skin, and moderate in the tumor of S180 bearing mice. MMC was inactivated strongly in the homogenates of the liver and kidney, and moderately in the heart and intestine of human tissues. The inactivation was enhanced by the addition of NADPH, vitamin B6, glutathione, etc. The blood level of KW-2083 in patients and mice decreased more rapidly than MMC. T 1/2 beta of KW-2083 in patients after iv injection at 70, 40 and 20 mg/body was about 18 minutes. The tissue level of KW-2083 in S 180 bearing mice was the highest in the lung and skin, followed by the kidney and tumor. The elimination rate of the drug from each tissue was more rapid than that of MMC. KW-2083 was highly excreted into the bile and more highly inactivated in the homogenates of the liver, kidney, muscle, etc. as compared with MMC. These pharmacokinetic behaviours of KW-2083 might be related to the lower toxicity and higher therapeutic ratio in experimental animals.
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PMID:[Pharmacokinetics of mitomycin C and its derivative (KW-2083)]. 682 Sep 13

Procion dye - agarose matrices were investigated for isolation of dihydrofolate reductase (FAH2R) from Walker 256 carcinosarcoma. Cibacron blue F3GA, Procion blue MX4GD, Procion blue HERD, and Procion red H3BN covalently bound to agarose adsorbed greater than 85% of pure FAH2R from 100 mM imidazole buffer, pH 6.3, and this enzyme was specifically and quantitatively eluted with 1 mM folate. The capacity and selectivity of the dye-agarose matrices were greater at low dye incorporation. Difference spectroscopy of the FAH2R - Cibacron blue F3GA complex indicated that 2 mol of the dye were bound in hydrophobic environments with each mole of the enzyme. NADPH and folate (at twofold molar excess over enzyme) or 1 M KCl displaced only 1 mol of Cibacron blue F3GA. This dye interacted stoichiometrically in a specific manner with the active site of FAH2R probably spanning the folate and NADP binding sites. The second dye molecule appears to be bound in a nonspecific hydrophobic manner. Selected Procion dye - agarose matrices can be used for partial purification of FAH2R from tumor homogenate.
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PMID:Procion dyes as affinity ligands and reporter groups for dihydrofolate reductase from Walker 256 carcinoma. 721 92

Mitomycin C (MMC) is a bioreductive antitumor agent that is activated by NADPH:cytochrome P450 reductase (EC 1.6.2.4) and NAD(P)H:(quinone acceptor) oxidoreductase (EC 1.6.99.2) (DT-diaphorase). DT-diaphorase is a two-electron reducing enzyme that is induced by a variety of chemicals, including quinones. Doxorubicin (DOX) is an anthraquinone antitumor agent that has been used clinically with MMC for combination chemotherapy in breast cancer. In this study, we investigated whether DOX could selectively induce DT-diaphorase in tumor cells and whether combining this agent with MMC in an appropriate schedule could produce synergistic antitumor activity. Treatment of EMT6 murine mammary tumor cells with DOX resulted in a 40% increase in DT-diaphorase activity in these cells, but had no effect on this enzyme in murine bone marrow cells. Combination therapy with DOX and MMC produced a 1.4-fold level of synergistic cell kill in the tumor cells, but a similar level of synergy was also observed in normal bone marrow cells. Thus, DOX can selectively induce elevated levels of DT-diaphorase in tumor cells; however, the synergy observed by combining this agent with MMC appears to be unrelated to the induction of DT-diaphorase.
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PMID:Induction of DT-diaphorase by doxorubicin and combination therapy with mitomycin C in vitro. 748 45

The sources of iron (Fe) and reductant required for DNA strand breakage by the antitumor drug bleomycin (Blm), H2O2 and ascorbate were investigated using nuclei instead of whole cells in order to study a simpler, related system that was subject to better control and easier chemical manipulation. Ehrlich ascites tumor cells were isolated and treated directly on filters, and analysed for DNA damage by alkaline and nondenaturing elution. Extraction and treatment buffers were depleted of trace Fe by passage through Mg(OH)2 gel. Nuclei were treated for 1 hr at 37 degrees. High levels of single- and double-strand breakage were obtained using Fe(III)Blm in the range 0.01 to 0.08 microM. In contrast, Blm was effective only at two orders of magnitude greater concentration. Cu(II)Blm was totally ineffective in causing damage. Depletion of nuclear protein thiols with N-ethylmaleimide reduced double-strand breakage at the upper end of the FeBlm concentration-response curve. A 1 mM concentration of NADPH or NADH greatly increased the extent of double-strand breakage by 0.01 microM FeBlm, suggesting roles for cytochrome P450 or cytochrome b5 reductase in strand breakage. Fe(III)ATP (1:20 metal to ligand and 50 microM in Fe) and Fe(III)EDTA (1:2 metal to ligand and 50 microM in Fe) did not cause single-strand breaks. In the absence of added Fe, H2O2 or ascorbic acid (50 microM) caused less than one Gy-equivalent single-strand breakage. Addition of ascorbate plus Fe(III)ATP or Fe(III)EDTA produced breakage beyond the capacity of alkaline elution to analyse (5-6 Gy). Overall, the results indicate that Fe, which may contribute to DNA damage by Blm and forms of activated oxygen within cells, is not strongly bound in the nucleus and that nuclear thiols other than glutathione contribute reducing equivalents to Fe(III)Blm for the DNA damaging chemistry.
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PMID:DNA strand breakage in isolated nuclei subjected to bleomycin or hydrogen peroxide. 752 Jun 97

Nitric oxide (NO) produced by endothelial cells (EC) has been shown to exert cytotoxic activity on tumor cells. In order to analyze events involved in brain metastasis, the modulation of NO production in rat-brain-derived EC was investigated. NO release was increased by tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1 beta, lipopolysaccharide or forskolin in EC219 cells, a rat-brain-microvessel-derived EC line. Dexamethasone decreased NO release by cytokine-activated EC219 cells. Tumor cells (DHD/K12/PROb, a rat colon-carcinoma cell line) were highly adherent to EC219 cells, and adhesion was not modified by TNF-alpha plus IFN-gamma, or by dexamethasone. Addition of tumor cells or tumor-cell-conditioned medium significantly inhibited NO release induced by any of the stimuli examined, but only if added during the initial phase of endothelial-cell activation. Tumor-derived suppression of NO release was also observed in primary cultures of cerebral EC. NO synthase (NOS) activity in cytosol extracts of the cerebral EC line was Ca(2+)-independent and required both NADPH and tetrahydrobiopterin. NOS activity was increased by TNF-alpha and IFN-gamma, and significantly reduced by tumor-cell-conditioned medium. These results suggest that rat colon-carcinoma cells may have developed a protective mechanism involving the release of (a) soluble factor(s) which inhibit(s) NO production by cerebral EC.
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PMID:Tumor cells suppress cytokine-induced nitric-oxide (NO) production in cerebral endothelial cells. 752 97

The nitric oxide synthases (NOS) are a family of related enzymes which regulate the production of NO, a free radical gas implicated in a wide variety of biological processes. Vasodilation and increased tumor blood flow, increased vascular permeability, modulation of host tumoricidal activity, and free radical injury to tumor cells and adjacent normal tissues are pathophysiological features of malignant tumors that may be mediated by NO. We examined human brain tumors for three NOS isoforms and NADPH diaphrase, a histochemical marker of NOS activity in the brain. We detected increased expression of the brain and endothelial forms of NOS [NOS I and NOS II, respectively (C. Nathan and Q. Xie. Cell, 78: 915-919, 1994)] in astrocytic tumors, and the highest levels of expression was found in higher grade tumors. Each of these two isoforms was found in tumor cells and tumor endothelial cells. The macrophage isoform of NOS (NOS III) was less frequently detected and expressed at a lower level, predominantly in tumor endothelial cells. NADPH diaphorase staining for NOS activity paralleled this pattern of NOS expression. Western blot analysis of tumor tissues for these NOS isoforms confirmed these observations. Our data indicate that malignant central nervous system neoplasms express unexpectedly high levels of NOS and suggest that NO production may be associated with pathophysiological processes important to these tumors.
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PMID:Expression of nitric oxide synthase in human central nervous system tumors. 753 13

Aldehyde dehydrogenase (ALDH) is well known for its involvement in the resistance of tumor cells to cyclophosphamide (CPA) and its activated derivatives, such as 4-hydroperoxy-CPA (4HC). The role of other drug-metabolizing enzymes such as glutathione S-transferase (GST) in CPA resistance is, however, less certain. In the present study of a human breast cancer cell line (MCF-7) exhibiting about 6-fold resistance to 4HC (MCF/HC), cellular levels of glutathione (GSH) were increased 1.4-fold, while cytosolic GST and ALDH activities were increased 2.7- and 7.2-fold, respectively, relative to the MCF-7 parental line. No significant changes in glutathione peroxidase and NADPH cytochrome P450 reductase activity, and no increase in microsomal GST and GST pi mRNAs were found in the resistant cells. Treatment with the ALDH substrate octanal sensitized the cells to the cytotoxic effects of 4HC to a modest extent in both MCF-7 and MCF/HC cells [dose modification factor (DMF) of 1.4 and 1.6, respectively]. Depletion of GSH by treatment with the GSH synthesis inhibitor buthionine sulfoximine (BSO) enhanced the cytotoxic effect of 4HC to a similar extent in both cell lines. By contrast, ethacrynic acid, which inhibited GST activity by > 85% in MCF-7 and MCF/HC cell extracts without depletion of GSH, sensitized the resistant but not the parental cells to 4HC cytotoxicity, indicating the importance of GST as a determinant of 4HC resistance in these cells. This conclusion is supported by the observation that in MCF/HC cells, ethacrynic acid in combination with BSO increased the DMF 3-fold higher than did BSO or EA alone, while in the parental MCF-7 cells ethacrynic acid with BSO had no significant chemosensitization effect over BSO alone. These studies establish that in addition to ALDH, GST overexpression can contribute to acquired resistance of tumor cells to 4HC and, furthermore, suggest that modulators that target the GSH/GST system could be useful in overcoming CPA resistance in the clinic.
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PMID:Identification of glutathione S-transferase as a determinant of 4-hydroperoxycyclophosphamide resistance in human breast cancer cells. 778 10

The present study was designed to evaluate whether vitamin E could be a useful chemopreventive agent to reduce spontaneous lung tumorigenesis in mice. Starting at 6 weeks of age, groups were divided into three groups, i.e. A/J mice fed a control diet (A/J control), A/J mice fed a vitamin E-supplemented diet (A/J vitamin E) and ddY mice fed a control diet (ddY control). At the 28th experimental week, nuclear NADPH-driven active oxygen generation, thiobarbituric acid reactive substances (TBARS) and DNA single strand breaks (DNA-SSB) in A/J mice fed a control diet were significantly higher than those in the ddY control group. A/J mice fed Vitamin E for 28 weeks could decrease the levels of TBARS and DNA-SSB with a significant difference, as compared with those in A/J control mice. The nuclear alpha-tocopherol levels in A/J controls were significantly lower than those in ddY controls, on the contrary, the vitamin feeding to A/J mice increased nuclear alpha-tocopherol levels more than that in the ddY controls. At the 40th experimental week, lung tumor incidence and tumor multiplicity (percentage of mice with tumors) in A/J controls were reduced and brought close to those in ddY control mice by vitamin E. Then the alpha-tocopherol level in plasma of A/J controls was significantly lower than the level in plasma of ddY controls, and the level in tumor-bearing mice in A/J controls also showed a lower level with significant difference as compared to that in non-tumor-bearing mice of A/J controls. These results suggest that the difference in susceptibility to spontaneous lung tumorigenesis between A/J and ddY mice partly depends on the difference of oxidative stress on the pulmonary nuclei, and vitamin E can act as a useful chemopreventive agent to reduce spontaneous lung tumorigenesis in mice.
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PMID:Vitamin E acts as a useful chemopreventive agent to reduce spontaneous lung tumorigenesis in mice. 781 42

Human antioxidant-response element (hARE) containing two copies of the AP1/AP1-like elements arranged as inverse repeat is known to mediate basal and beta-naphthoflavone-induced transcription of the type 1 NAD(P)H:quinone oxidoreductase (NQO1) gene. Band-shift assays revealed that beta-naphthoflavone increased binding of nuclear proteins at the hARE. Super shift assays identified Jun-D and c-Fos proteins in the band-shift complexes observed with control and beta-naphthoflavone-treated Hepa-1 nuclear extracts. Hepa-1 cells stably transformed with hARE-tk-chloramphenicol acetyl transferase (CAT) recombinant plasmid were used to demonstrate that, in addition to beta-naphthoflavone, a variety of antioxidants, tumor promoters and hydrogen peroxide (H2O2) also increased expression of hARE-mediated CAT gene. beta-naphthoflavone induction of the CAT gene expression in Hepa-1 cells was found insensitive to inhibitors of protein kinase C and tyrosine kinases. However, binding of regulatory proteins at the hARE and the CAT gene expression in Hepa-1 cells were increased by dithiothreitol, 2-mercaptoethanol and diamide. Treatment of the Hepa-1 cells with N-ethylmaleimide reduced binding of proteins at the hARE and interfered with expression and beta-naphthoflavone induction of the CAT gene. These results suggested a role of sulfhydryl modification of hARE binding (Jun and Fos) proteins which mediate basal and induced expression of the NQO1 gene. We also report that in-vitro-translated products of the proto-oncogenes, Jun and Fos, bind to the hARE in band-shift assays. The incubation of Jun and Fos proteins with small amounts of nuclear extract from dimethylsulfoxide-treated (control) or beta-naphthoflavone treated Hepa-1 cells prior to band-shift assays increased the binding of Jun and Fos proteins to the hARE. Interestingly, the increase in binding of Jun and Fos proteins to the hARE was more prominent with beta-naphthoflavone-treated nuclear extract as compared to the control nuclear extract. In addition, incubation of control nuclear extract with beta-naphthoflavone, microsomes and NADPH increased the binding of Jun and Fos proteins to the hARE. Evidence from in vitro studies indicate the presence of unknown nuclear factor(s) that receive signals from metabolites of beta-naphthoflavone and modulate Jun and Fos binding to the AP1 site contained within the hARE.
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PMID:Human antioxidant-response-element-mediated regulation of type 1 NAD(P)H:quinone oxidoreductase gene expression. Effect of sulfhydryl modifying agents. 795 57


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