Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of hyperthermia and environmental pH on proteolytic activity was studied in murine ascites tumor cells in vitro. PNJ ascites tumor cells were incubated with [125I]cytochrome c at 42.5 or 37 degrees C in a modified Krebs-Ringer buffer adjusted to pH 7.2 or 6.4. Incubation at normal temperature at pH 6.4 and 7.2 or at 42.5 degrees C and pH 7.2 resulted in identical protein digestion. However, hyperthermic incubation at pH 6.4 resulted in a significant increased activity. This was also observed after only 1 hour of hyperthermic incubation followed by subsequent incubation in an acidic environment at normal temperature. The increased proteolytic activity following hyperthermic treatment under acidic conditions may support the hypothesis that increased lysosomal activity is of primary importance in the hyperthermic tumor-cell destruction in vivo.
J Natl Cancer Inst 1977 Apr
PMID:Effect of hyperthermia and environmental acidity on the proteolytic activity in murine ascites tumor cells. 1 31

Weanling male Sprague-Dawley rats were fed either a nutritionally complete synthetic diet (Diet 1) or a diet marginally deficient in choline and methionine, and lacking folacin (lipotrope deficient, Diet 2) to determine the role of hepatic mixed-function oxidase metabolism of aflatoxin B1 (AFB1) in the Diet 2-induced enhancement of AFB1 hepatocarcinogenesis previously reported. Hepatic microsomal mixed-function oxidase activities, as assayed by ethylmorphine N-demethylation, ethoxycoumarin O-dealkylation, cytochrome c reduction, AFB1 metabolism, and cytochrome P-450 content, were all depressed by Diet 2. Furthermore, the proportion of an i.p. dose of AFB (1 mg/kg) that became covalently bonded to DNA and RNA was similarly reduced when measured 6 hr after administration. The formation of AFB1-protein adducts was not influenced by dietary treatment. The depression of DNA and RNA adduct formation in the Diet 2 animals was probably related to the lower mixed-function oxidase activities and not to an alteration of glutathione levels, which remained unchanged by dietary treatment. These results suggest that the marginally lipotrope-deficient diet does not enhance tumor formation through an increased microsomal activation of AFB1. Alternative hypotheses without data are suggested.
Cancer Res 1978 Dec
PMID:Dietary lipotropes, hepatic microsomal mixed-function oxidase activities, and in vivo covalent binding of aflatoxin B1 in rats. 8 78

Previously, we reported that the rate of metabolism of methyl sterol intermediates of cholesterol biosynthesis by broken-cell preparations of Morriss hepatoma 7777 is very slow, whereas the intact tumors are known to synthesize cholesterol quite efficiently. Active preparations have now been obtained by substitution of pyrophosphate for phosphate buffer. Although substitution of pyrophosphate buffer markedly enhances microsomal methyl sterol demethylation rates 3- to 4-fold in hepatoma 7777, other microsomal enzymes and electron carriers in either liver or a more slowly growing hepatoma appear to be unaffected by pyrophosphate. Several properties of the active microsomal methyl sterol demethylase have now been compared for control rat liver, host liver, tumor 7777, and tumor 5123C. Conditions necessary for the assay of initial velocities of enzymic reactions in the tumor microsomes have been established with respect to the amount of protein, time-course, concentrations of cofactors and substrate, pH, and other variables. The K'm and the responses to the variables studied above are very similar for methyl sterol demethylase of microsomes isolated from control liver, host liver, tumor 5123C, and tumor 7777. The multienzymic demethylase in the various preparations has been found to be inhibited similarly by in vitro additions of cyanide, cytochrome c, and bile salts. Thus, the enzymes of the microsomal-bound 4-methyl sterol demethylase of cholesterol biosynthesis appear to be very similar in liver and these 2 Morris hepatomas. When xenobiotic inducers of microsomal oxidases, such as phenobarbital and methylcholanthrene, are administered to normal and tumor-bearing rats, elevated rates of methyl sterol demethylation are observed with isolated liver microsomes obtained from both normal and tumor-bearing rats. Similar increases are not observed in the tumors. Furthermore, daily administration of an intestinal bile acid sequestrant elevates hepatic methyl sterol demethylase, but statistically significant changes were not observed in tumors 7777 and 5123C. Since the enzymes of methyl sterol demethylase appear to be grossly similar in liver and these hepatomas, regulation of the activity of the multienzymic system contained in the tumors may be altered. On the other hand, these agents in vivo simply may not affect liver and the hepatomas similarly, due to a lack of uptake of the foreign substances by the tumor that has been transplanted to the thighs.
Cancer Res 1976 Feb
PMID:Characterization of microsomal methyl sterol demethylase in two Morris hepatomas. 17 91

The superoxide anion-generating capacity of human blood monocytes was measured by a sensitive and rapid method established by taking advantage of the fact that the generation of superoxide anions by monocytes was markedly enhanced by the combined stimulation of the cells with cytochalasin-E and wheat germ agglutinin. The activity was expressed by the initial rate of cytochrome c reduction after the addition of wheat germ agglutinin. The rate obtained with normal human monocytes was 0.73 +/- 0.19 nmol/min/10(5) monocytes (mean +/- SD, n = 10). Because of its sensitivity, the method required only 10(5) monocytes and can be used to follow the monocyte function in various patients. Preliminary data obtained with 15 cases of advanced cancer patients (0.29 +/- 0.10 nmol/min/10(5) monocytes) suggested a possible decrease of the superoxide-generating activity, at least in some state of cancer patients. It appears that measurement of superoxide-generating activity will be meaningful to monitor monocyte function.
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PMID:Sensitive and rapid method for determination of superoxide-generating activity of blood monocytes and its use as a probe for monocyte function in cancer patients. 23 38

Trout liver microsomes contained as 0.40 nmole of cytochrome P-450 per mg of protein and a NADPH-cytochrome c reductase activity of 23 nmoles of cytochrome c reduced per mg of protein per min at 22 degrees. Associated with these was a high benzo(a)pyrene hydroxylase activity, which required NADPH and O2 and was inhibited by CO. With thin-layer chromatography, at least five metabolites could be identified (including dihydrodiols, phenols, and quinones of benzo(a)pyrene). Inhibitors such as 2-diethylaminoethyl-2,2-diphenylvalerate, aminopyrine, metyrapone, pyridine, n-octylamine, and 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane were relatively ineffective in inhibiting trout benzo(a)pyrene hydroxylase. Typical inhibitors of 3-methylcholanthrene-induced cytochrome (P-448), such as alpha-naphthoflavone, zoxazolamine, and testosterone, were effective, however. With benzo(a)pyrene it was possible to induce type I spectral change in trout cytochrome P-450. In spite of the many enzymatic characteristics of cytochrome P-448, trout cytochrome P-450 had maximum absorbance at 450.6 nm. when in reduced form and complexed with CO. the ethyl isocyanide gave an interaction spectrum with reduced trout liver cytochrome P-450 resembling that of control rat.
Cancer Res 1977 Oct
PMID:Characterization of benzo(a)pyrene hydroxylase of trout liver. 40 87

Several studies have indicated a correlation between the presence of inflammation and the development of cancer. The aim of our study was to determine if pulmonary neutrophils could transform the proximate respiratory carcinogen (+-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (B[a]P-7,8-diol), to an ultimate carcinogenic metabolite via myeloperoxidase (MPO). To test this hypothesis, virus-free male DBA/2 mice were exposed by inhalation to the Gram-negative bacteria Proteus mirabilis for 1 h. For various time points post-exposure, bronchoalveolar lavage (BAL) was performed to determine total and differential cell counts, cellular MPO activity and production of superoxide. Twelve hours after the exposure, cellular activity of MPO as well as percentage and total number of polymorphonuclear leukocytes peaked and declined thereafter. At this same time point, cells from BAL exhibited increased release of superoxide, as measured by reduction of cytochrome c, after addition of soluble or particulate stimuli, 12-O-tetradecanoylphorbol-13-acetate (TPA) or opsonized zymosan respectively. These cells also elicited biotransformation of B[a]P-7,8-diol as evidenced by enhanced B[a]P-7,8-diol-derived chemiluminescence, tetraol formation and covalently bound adduct formation to exogenous DNA upon addition of TPA or opsonized zymosan. Moreover, the cell-free BAL fluid of infected mice contained substantial MPO activity in comparison to that of uninfected animals. Also, MPO enhanced the binding of B[a]P-7,8-diol to lung DNA in vitro. Unlike previous work emphasizing the potential roles of oxygen free radicals in tumor promotion, our results indicate a role of neutrophilic MPO in the initiation of carcinogenesis.
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PMID:Myeloperoxidase-enhanced formation of (+-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene-DNA adducts in lung tissue in vitro: a role of pulmonary inflammation in the bioactivation of a procarcinogen. 132 50

A mitomycin C (MMC)- and porfiromycin (PFM)-resistant subline of the HCT 116 human colon-cancer cell line was isolated after repeated exposure of HCT 116 cells to increasing concentrations of MMC under aerobic conditions. The MMC-resistant subline (designated HCT 116-R30A) was 5 times more resistant than the parent cells to MMC and PFM under aerobic conditions. Both the MMC-resistant cells and the parent HCT 116 cells accumulated similar amounts of PFM by passive diffusion, but levels of macromolecule-bound PFM were about 50% lower in the resistant cell line, implying a decrease in PFM reductive activation in the resistant cells. The finding that microsomes from either sensitive or resistant cells showed an equal ability to reduce MMC and PFM indicated that the activity of NADPH cytochrome P-450 reductase (EC 1.6.2.4) was not changed in the resistant subline. Soluble extracts of HCT 116 cells reduced MMC and PFM more effectively at pH 6.1, and NADH and NADPH were utilized equally well as electron donors under both aerobic and anaerobic conditions. These data suggest that quinone reductase (EC 1.6.99.2; DT-diaphorase) in soluble extracts is responsible for the reduction of MMC. Quinone reductase activities in soluble extracts of HCT 116-R30A cells for the reduction of dichlorophenol indophenol (DCPIP) and menadione-cytochrome c at optimal pHs were decreased by 95% as compared with those obtained in parent cells. However, the MMC-reducing activity of HCT 116-R30A soluble extracts was only 50% lower than that of the parent cell extracts. The kinetic constants (Km, Vmax) found for quinone reductase in the two cell lines with respect to the substrates DCPIP and menadione differed. Two species of mRNA for quinone reductase (2.7 and 1.2 kb) were detected in both cell lines, and there was no detectable difference between parent and resistant cells in the steady-state level of either of these mRNA species. Furthermore, incubation with the quinone reductase inhibitor dicoumarol rendered HCT 116 cells more resistant to MMC. Alteration of the quinone reductase activity in HCT 116-R30A cells appears to be the mechanism responsible for their resistance to MMC and PFM.
Cancer Chemother Pharmacol 1992
PMID:The role of NAD(P)H:quinone oxidoreductase in mitomycin C- and porfiromycin-resistant HCT 116 human colon-cancer cells. 145 56

Dinitropyrenes are mutagenic environmental pollutants. Of these compounds, 1,6-dinitropyrene is a potent tumorigen while 1,3-dinitropyrene appears to be weakly or non-tumorigenic. Two-electron reduction of dinitropyrenes yields nitro-nitrosopyrenes, which have been shown previously to be the major aerobic metabolites of these compounds in vitro. Further reduction of nitrosopyrenes is required for their activation to a DNA-reactive N-hydroxylamines. In this work, 1-nitro-3-nitrosopyrene was synthesized and the electrochemical and enzyme-catalyzed reduction of 1-nitro-3-nitrosopyrene has been compared with that of 1-nitro-6-nitrosopyrene. As determined by cyclic voltammetry, the reduction potentials of 1-nitro-3-nitrosopyrene, 1-nitro-6-nitrosopyrene and their parent dinitropyrenes were similar, although 1-nitro-3-nitrosopyrene did have a slightly more negative cathodic peak potential than the other three compounds. The NADPH-mediated reduction of 1-nitro-6-nitrosopyrene to intermediates which reduce succinoylated cytochrome c was faster than that of 1-nitro-3-nitrosopyrene. In the presence of rat liver microsomes or cytosol, the reduction of 1-nitro-6-nitrosopyrene was faster than that of 1-nitro-3-nitrosopyrene. These differences in the rates of nitro-nitrosopyrene reduction may be one factor contributing to the lower tumorigenic potential of 1,3-dinitropyrene relative to 1,6-dinitropyrene.
Cancer Lett 1992 Jul 31
PMID:Comparative reduction of 1-nitro-3-nitrosopyrene and 1-nitro-6-nitrosopyrene: implications for the tumorigenicity of dinitropyrenes. 151 10

Cytochrome c from various sources, such as Candida krusei, yeast, horse, and cattle, was found to be recognized by human monoclonal antibody HB4C5 specific to lung cancer. Therefore, the cytochrome c was applied to the measurement of antibody amount in patient sera with a similar reactivity to the antibody HB4C5 for serodiagnosis of cancer. The cytochrome c from Candida krusei was most valuable for the serodiagnosis of various cancers, and the yeast cytochrome c was also useful. However, horse and bovine cytochrome c did not react with antibody of the cancer patients. By using Candida cytochrome c lung, bile duct, esophagus, and liver cancers were detected at high rates of more than 50%. In the case of lung cancer, the detection rates of small-cell, squamous, large-cell and adenocarcinoma were 78%, 63%, 100%, and 34%, respectively. The rate for small-cell carcinoma was higher than that with the currently used NSE assay system, and the rate for squamous carcinoma was comparable to that with the SCC assay system, although the system using cytochrome c did not show similar reactivity to that with the SCC system. Furthermore, lung cancer was detected at early stages by using cytochrome c, and even in the case of adenocarcinoma, the rate at early stages with the cytochrome c system was higher than that with the CEA assay system. On the other hand, false positive rates of benign diseases and normal were low--8% and 2%, respectively.
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PMID:Serodiagnosis of cancer by using Candida cytochrome c recognized by human monoclonal antibody HB4C5. 165 88

EO9 [3-hydroxymethyl-5-aziridinyl-1-methyl-2-(H-indole-4, 7-indione)-propenol] is a novel indoloquinone structurally related to mitomycin C, a quinone anticancer drug that requires reductive bioactivation. NAD(P)H: (quinone-acceptor) oxidoreductase (quinone reductase, DT-diaphorase, EC 1.6.99.2) is an obligate 2-electron donating enzyme that can reduce a variety of quinones resulting either in bioactivation or bioprotection. Using quinone reductase (QR) preparations from rat Walker 256 mammary tumor cells and human HT29 colon carcinoma cells, we have characterized the role of this enzyme in EO9 reductive metabolism. QR activity was assayed under optimal conditions by following cytochrome c reduction at 550 nm in the presence of enzyme, quinone substrate, NADH, and bovine albumin, and confirmed by loss of EO9 absorbance at 550 nm. Both the rat and human tumor cell enzymes catalyzed reduction of the benchmark quinone menadione with a similar Km of 1.4-3.1 microM, although the Vmax was 7 to 8-fold lower for the human preparation. EO9 was readily reduced by the rat Walker QR. The mean Km was about 5-fold higher than for menadione at around 15 microM and the Vmax was 6-fold lower at around 2.5 mumol of cytochrome c reduced mg-1 of protein. EO9 was also metabolized by QR from HT29 human colon carcinoma cells but rather less efficiently than by the rat tumor enzyme. For example, the rate was 6-fold lower than that for the Walker tumor enzyme at 100 microM substrate concentration after correcting for the 7- to 8-fold difference in specific activity for the two preparations.(ABSTRACT TRUNCATED AT 250 WORDS)
Cancer Commun 1991 Jul
PMID:The role of NAD(P)H: quinone reductase (EC 1.6.99.2, DT-diaphorase) in the reductive bioactivation of the novel indoloquinone antitumor agent EO9. 171 84


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