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)

Previous studies with Adriamycin-sensitive and -resistant (ADRR) MCF-7 human breast tumor cell lines indicated that Adriamycin formed significantly less hydroxyl radical (.OH) as the result of enhanced detoxification of reactive oxygen intermediates in the ADRR cell line. In order to further define the sites of drug activation and the role of detoxification mechanisms in free radical levels, subcellular fractions were isolated from these two cell lines and free radical formation in the presence of Adriamycin was examined by using electron spin resonance spectroscopy. Studies reported here show that considerable NADPH-cytochrome P-450 reductase and NADH dehydrogenase activities were present in microsomes and mitochondria, respectively, and in nuclei obtained from these cells, and the relative activity of NADH dehydrogenase was 2-fold higher in the mitochondrial fraction of ADRR cells compared to the mitochondrial fraction from the parental wild type cells. In the presence of Adriamycin and a reducing cofactor (NADPH or NADH), Adriamycin semiquinone free radical, superoxide anion, and .OH were detected in all these fractions. Although only a small difference in the relative amount of oxy radical formation was detected in tumor microsomes, both mitochondria and nuclei of ADRR cells showed an overall 2-fold decreased formation of oxy radicals. The formation of the free radicals was significantly inhibited by superoxide dismutase, catalase, and dimethyl sulfoxide, indicating that free .OH generation was both superoxide and hydrogen peroxide dependent. The addition of purified glutathione peroxidase likewise inhibited .OH formation in a dose-dependent fashion. Similarly, when the lysate from ADRR cells, which contains 12- to 14-fold more glutathione peroxidase than Adriamycin-sensitive cells, was added to reaction mixtures containing Adriamycin-sensitive cells and Adriamycin, the .OH formation was diminished. Decreased free radical formation in nuclei and mitochondria, as a result of detoxification of hydrogen peroxide by glutathione peroxidase, may be significant in the protection of ADRR cells from Adriamycin-induced cell killing.
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PMID:Adriamycin activation and oxygen free radical formation in human breast tumor cells: protective role of glutathione peroxidase in adriamycin resistance. 254 60

Cancer research in drug targeting has focused on the use of monoclonal antibody conjugates of drugs. This paper discusses the use of ligand conjugates of drugs to deliver to receptors on cancer cells. We have used transferrin coupled to adriamycin, and report these conjugates specifically bind and kill cancer cells in culture. Our studies of the mechanism show targeted plasma membranes are compromised for NADH ferricyanide reduction, and targeted cells lose diferric transferrin reductase activity. These results indicate that the binding of transferrin-adriamycin conjugates to transferrin receptors on either isolated plasma membranes or viable tumor cells causes an inhibition of redox reactions that are essential for growth. Since transferrin receptors are endocytosable, ligand-drug conjugates also are delivered to the interior of targeted cells where other mechanisms of killing can be employed. This novel method of drug delivery circumvents the need for monoclonal antibodies, and more investigation of the system may allow a controlled clinical study of its effectiveness.
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PMID:Recent advances in cancer research: drug targeting without the use of monoclonal antibodies. 264 Apr 41

A non-invasive and non-destructive fluorescence technique developed recently for an in situ detection of melanomas has been applied for determining in vitro dysplasia and invasive carcinomas in the cervix uteri. The cervices uteri exhibit a fluorescence band with a peak at about 475 nm if excited with 365 nm. The fluorescence intensity increases concomitantly with the degree of dysplasia, ranging from 30 counts/100 ms (healthy) to approximately 200 counts per 100 ms (CIN 3). At the rim of a malignancy, the intensity is 250 counts/100 ms and higher and decreases towards the healthy region. In the tumor region, the intensity is about zero or very small, at the most. The naturally occurring chromophore being responsible for the fluorescence observed seems to be NADH.
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PMID:Native fluorescence of the cervix uteri as a marker for dysplasia and invasive carcinoma. 275 94

The effect of t-butyl-4-hydroxyanisole (BHA), a widely used food antioxidant additive, on the culture growth, oxygen consumption, and redox state of some electron carriers of intact TA3 and 786A ascites tumor cells has been studied. BHA inhibited culture growth and respiration of these two tumor cell lines, by inhibiting the electron flow through the respiratory chain. Experiments to determine its site of action showed that BHA did not inhibit noticeably the electron flow through cytochrome oxidase, due to the ability of N,N,N',N'-tetramethyl-p-phenylenediamine to bypass the BHA inhibition of the respiration. Electron flow through the ubiquinone-cytochrome b-c1 complex also was unaffected by BHA; in fact, BHA failed to inhibit the oxidation of duroquinol. Spectrophotometric experiments are in accordance with studies carried out using synthetic electron donors. The redox state of NAD(P)+, determined in steady-state conditions, changed to a more reduced level, and the redox states of ubiquinone, cytochrome b, cytochromes c + c1 and cytochromes a + a3 changed to a more oxidized level. These observations suggest that the electron transport in the tumor mitochondria was inhibited by BHA at the NADH-dehydrogenase-ubiquinone level (energy-conserving site 1). These findings could explain, in part, the cytotoxic effect of BHA.
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PMID:t-butyl-4-hydroxyanisole as an inhibitor of tumor cell respiration. 281 35

LM fibroblasts grown in a chemically-defined, serum-free medium readily incorporated choline or one of three analogues of choline, namely N,N-dimethylethanolamine, N-monomethylethanolamine, or ethanolamine into membrane phospholipids. The effect of these phospholipid manipulations in vitro on tumor growth and metastasis was examined in nude mice. Serum and choline-fed cells most frequently metastasized (74% and 68%, respectively), while frequency of lung metastasis was 46%, 42% and 17% in mice injected with cells fed with dimethylethanolamine, monomethylethanolamine, and ethanolamine, respectively. Metastases from cells cultured with serum, choline or dimethylethanolamine, but not from monomethylethanolamine or ethanolamine, were extensive and highly invasive. The specific activity of the (Na+ + K+)-ATPase but not of 5'-nucleotidase was significantly decreased in local tumor plasma membranes from choline analogue-fed cells as compared to tumor plasma membranes from choline-fed cells. When compared to the choline-fed tumor cells, the specific activities of three mitochondrial enzymes, namely NADH dependent, rotenone insensitive NADH-dependent, and rotenone sensitive NADH-dependent cytochrome-c reductase, were significantly increased in the choline analogue-supplemented cells. The arachidonic acid content of phosphatidylcholine in plasma membranes, microsomes, and mitochondria was significantly decreased in tumor membranes from choline analogue-fed cells as compared to tumor membranes from choline-fed cells. As compared to local tumor plasma membranes, the lung metastasis plasma membranes had elevated (Na+ + K+)-ATPase specific activity, phospholipid oleic and arachidonic acid content, and fluidity. In contrast, the 5'-nucleotidase specific activity, the content of cholesterol, phospholipid, and phosphatidylethanolamine were decreased in lung metastasis plasma membranes. In summary, membrane alterations of LM tumor cells in vitro (1) were not completely reversed in vivo, and (2) affected metastatic ability.
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PMID:Local and metastatic tumor growth and membrane properties of LM fibroblasts in athymic (nude) mice. 283 81

The IMP dehydrogenase of Tritrichomonas foetus, a parasitic protozoan incapable of de novo biosynthesis of purine nucleotides, has been purified about 1000-fold to apparent homogeneity. The purified enzyme demonstrated a 20-fold higher substrate turnover rate than the pure IMP dehydrogenase from sarcoma ascites tumor cells. It has a subunit molecular weight of 58,000, aggregates to a size of 380,000 at low ionic strength, and partly dissociates to a molecular weight of 270,000 in high salt concentrations. Unlike the IMP dehydrogenase of bacteria and mammals, the T. foetus enzyme does not require K+ for activity. The analysis of initial velocity and product inhibition data is consistent with a sequential, ordered bi bi kinetic mechanism for the parasite enzyme-catalyzed reaction, in which IMP binds before NAD+ and NADH is released before XMP. This is in contrast to the partially random mechanism of the bacterial enzyme which involves the formation of an enzyme-K+-(IMP) complex. Mycophenolic acid inhibits T. foetus IMP dehydrogenase uncompetitively versus both IMP and NAD+ with an apparent Ki of 9 microM. This value, which is several hundred-fold higher than that for mammalian IMP dehydrogenase, suggests significantly different binding properties of the mycophenolic acid site in T. foetus IMP dehydrogenase, which might be amenable to specific inhibitor design.
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PMID:Purification, characterization, and kinetic analysis of inosine 5'-monophosphate dehydrogenase of Tritrichomonas foetus. 288 11

The proliferation of in vitro grown Ehrlich ascites tumor cells is inhibited by pyruvate concentrations greater than 2 mM. In the presence of 4-5 mM pyruvate the growth is reduced to about 50%, in the presence of 20 mM to about 5-10%. Viability of the cells is not severely affected. Increase of DNA corresponds to the cell growth. On recultivation in pyruvate free standard medium, growth is nearly normal. Flow cytometric analyses of the proliferation kinetics of the cells in the presence of 20 mM pyruvate revealed a retardation of the passage of all phases of the cell cycle. No phase specific effects could be detected though the S- and G2M-phase are more afflicted than G1. The growth inhibition of EAT cells by pyruvate seems to depend on the presence of glucose. Exogenous pyruvate (greater than 1-2 mM) causes an activation of pyruvate dehydrogenase, a reduction of lactate production from glucose and a stimulation of lipid biosynthesis; the NAD/NADH ratio of the cells is reduced and a rise of glycolytic intermediates beyond glyceraldehyde-3-phosphate dehydrogenase is observed. Maximal activation of pyruvate dehydrogenase by non toxic concentrations of dichloroacetate is also accompanied by an inhibition of cell growth. It is suggested that an increase of glyceraldehyde-3-phosphate level and the changes in the redox state of the cells are of relevance for the inhibition of cell growth by pyruvate. 100-500 microM exogenous glyceraldehyde-3-phosphate strongly inhibited cell growth.
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PMID:Proliferation kinetics and metabolic features of in vitro grown Ehrlich ascites tumor cells in the presence of exogenous pyruvate. 294 14

Gynecological, endocrinological and histological tests on a 19-year-old female patient led to the diagnosis of Sertoli-Leydig cell tumor (arrhenoblastoma) of intermediate differentiation. For enzyme histochemical purposes the tumor tissue, removed from the right ovary by laparatomy, was frozen in liquid nitrogen. The following enzymes were demonstrated: nonspecific esterases, 3 beta-hydroxysteroid dehydrogenase (HSDH), 17 beta-HSDH, 11 beta-HSDH, and NADH tetrazolium reductase. Cryostat sections, prefixed with formaldehyde vapors, were used to localize testosterone production immunohistochemically with the PAP method. A large number of pseudotubules with Sertoli cells were observed; the Leydig cells in the interstitial space were often arranged in the form of islands. Strong nonspecific esterase activity weak 3 beta-HSDH activity, moderate 17 beta-HSDH activity, and strong 11 beta-HSDH activity were observed largely in the Leydig cells. Testosterone synthesis, demonstrated immunohistochemically, took place predominantly in the Leydig cells, but also to a small extent in the Sertoli cells.
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PMID:Demonstration of hydroxysteroid dehydrogenases and testosterone in the Sertoli-Leydig cell tumor (androblastoma) tissue of the human ovary: an enzyme histochemical and immunohistochemical study. 298 72

In osteoclastic giant cells of six different tumors of bones and joints (fibrous dysplasia, proliferating giant cell tumor, malignant giant cell tumor, osteosarcoma after chemotherapy, malignant synovioma and Ewing's sarcoma) activities of tartrate-resistant acid phosphatase, NADH-tetrazolium-oxidoreductase and, in three of them, of non-specific esterase are determined by enzyme histochemical methods. Quantitative microphotometry makes it possible to determine relative enzyme activities in the cut sections of giant cells of different sizes. Giant cells of the various tumors reveal similar trends: With an increase in cell size, mean extinctions of NADH-tetrazolium-oxidoreductase and non-specific esterase decrease. Mean extinctions of tartrate-resistant acid phosphatase increase in cells of medium size, whereas the large cells reveal in part low activities. An additional ultrastructural examination of the giant cells in the proliferating giant cell tumor as well as in the osteosarcoma shows morphological signs of degeneration in the large cells. Electron probe microanalysis of the proliferating giant cell tumor exhibits evidence of phagocytosis of Ca and/or Fe containing particles. The similar size dependent reaction pattern of enzymes in osteoclastic giant cells of different tumors favors the concept of a common histogenesis, i.e. a host reaction.
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PMID:Size dependent enzyme activities of multinucleated (osteoclastic) giant cells in bone tumors. 303 7

In an attempt to characterize metabolism enzymes of the estrogen-induced kidney tumor in male Syrian hamsters, the activities of enzymes involved in drug and glutathione metabolism were determined in tumor tissue. Kidney tumors were induced in male Syrian hamsters by treatment with estradiol for 8 months. Cytochrome P-450 and cytochrome b5 concentrations in tumors were below detectable levels. However, when cytochrome P-450-mediated oxidation was analyzed by product formation assays, the oxidation of E-diethylstilbestrol to diethylstilbestrol-4',4"-quinone by tumor microsomes was 10-20% of the rate found in control microsomes. In kidney tissue surrounding estrogen-induced tumors, cytochrome P-450 and b5 contents were 50-60% less than those in untreated kidney. Activities of reducing enzymes of drug metabolism (cytochrome P-450, cytochrome b5 and NADH:cytochrome c reductases), glutathione metabolism enzymes (glutathione peroxidase, glutathione transferase, glutathione reductase, and gamma-glutamyl transpeptidase), and free radical scavenging enzymes (superoxide dismutase, catalase, and quinone reductase) in tumor were significantly lower than in untreated kidney tissue. The activities of these enzymes in renal tumor surrounding tissue were between those observed in tumor and control kidney. Glucose-6-phosphate dehydrogenase activity was increased by 50% in surrounding tissue and 430% in tumor compared to values in untreated controls. The decreased enzyme activity levels in hormone-exposed tissue surrounding tumors likely represented an adaptation of this tissue to the neoplastic environment induced by chronic estrogen treatment.
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PMID:Characterization of drug metabolism enzymes in estrogen-induced kidney tumors in male Syrian hamsters. 304 47


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