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)

The carcinogen 4-nitroquinoline 1-oxide (4-NQO) was found to rapidly deplete non-protein thiols (NPSH) from Ehrlich ascites tumor cells and V79 Chinese hamster fibroblasts. The effects of NPSH on 4-NQO metabolism were studied by measuring 4-hydroxyaminoquinoline 1-oxide formation, CN- -insensitive oxygen consumption, and reduction of ferricytochromes c + c1 in normal cells and in cells pretreated with the thiol reagent N-ethylmaleimide. Removal of thiols before treatment with 4-NQO resulted in increased production of 4-hydroxyaminoquinoline 1-oxide and increased production of nitro radicals. The NPSH thus appeared to play a significant role in 4-NQO detoxification. Glutathione, when present in culture medium during 4-NQO treatment, protected V79 cells from 4-NQO toxicity. Several mechanisms for reaction of 4-NQO with intracellular NPSH were indicated. Both V79 and Ehrlich cells contained appreciable amounts of glutathione S-transferase (EC 2.5.1.18), which catalyzes the nucleophilic substitution of the nitro group of 4-NQO with thiols. Greater thiol loss under oxic than under hypoxic conditions suggested oxidation by superoxide, peroxide, or hydroxyl radical formed in the course of 4-NQO reduction. In addition, reaction of thiols with nitro radicals or with nitrosoquinoline 1-oxide was indicated by the inhibitory effect of glutathione on oxygen consumption in solutions of 4-NQO and sodium ascorbate.
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PMID:Interactions of the carcinogen 4-nitroquinoline 1-oxide with the non-protein thiols of mammalian cells. 11 Apr 43

Ethylene dibromide (EDB), a known stomach carcinogen, and ethylene dichloride (EDC), which is carcinogenic to the liver, have been shown in in vitro experiments to bind covalently to stomach and hepatic microsomal proteins and to salmon sperm DNA. The binding of EDB or EDC with proteins was not significant when denatured microsomes were used or when DNA was used in the absence of microsomes. The binding of EDB to these macromolecules was augmented with increasing concentrations of microsomes. SKF-525A, an inhibitor of the microsomal metabolism of various substrates, significantly inhibited the binding of EDB to protein and DNA. These findings suggest that metabolic activation of EDB and EDC is required for their covalent binding to macromolecules. Glutathione and 1-methyl-2-mercaptolmidazole markedly decreased the binding of EDB, which indicated that a reactive electrophilic intermediate(s) of EDB is (are) involved in the binding. The binding of EDC to liver proteins of (C57BL/6 X C3//He)F1 mice, which are susceptible to liver tumor induction by EDC and to DNA, was significantly higher than the corresponding binding for Osborne-Mendel rats, a species not susceptible to liver tumor induction by this compound.
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PMID:Binding of carcinogenic halogenated hydrocarbons to cell macromolecules. 38 53

Ligandin is an abundant soluble protein of relatively short half life which is induced by many drugs and chemicals and stabilized in the absence of thyroid hormone. The protein is strategically concentrated in cells associated with transport and detoxification of a large variety of potential endogenous ligands such as bilirubin and perhaps heme, and exogenous, such as a multitude of drugs and chemicals. The protein is a dimer in rat liver. Whether it is a primary gene product or whether at least two genes are involved is not known. The protein has broad, low affinity catalytic activity for ligands having electrophilic groups and hydrophobic domains. It either catalyzes formation of GSH conjugates (e.g. bromosulphophthalein), noncovalently binds prior to biotransformation or excretion in bile (e.g. bilirubin), or covalently binds (e.g. activated carcinogens) potential ligands. Recent studies expand the scope of ligandinology to include its possible role in chemical carcinogenesis, diagnosis of inflammatory and neoplastic disease of the liver and kidney, and participation in intracellular transport. Although some of the roles that have been outlined are speculative, any single function is important. These are primitive enzymes and nonspecific binding proteins but "it is precisely their simplistic design that allows such protein serviceability".
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PMID:Ligandin: review and update of a multifunctional protein. 39 5

N-methyl-N-nitrosourea (MNU), N-(2-chloroethyl)-N'-(trans-4-methylcyclohexyl)-N-nitrosourea (methylCCNU), and N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) were examined for their effect on glutathione (GSH) levels of various tissues of normal and L1210-leukemic mice. BCNU produced significant decreases in the GSH levels of livers of both groups, but caused no change in the GSH content of the L1210 tumor or in the lungs. The GSH content of the kidneys of L1210 tumor-bearing mice, however, was significantly decreased by BCNU at early time points. A small increase in the liver content of oxidized glutathione could not account for the decrease content of GSH. Methyl CCNU and MNU were without effect on any of the tissues examined. These data are consistent with our previous observation that BCNU is a substrate for GSH S-transferase, and suggest that a GSH-dependent process is an important pathway for the metabolism of BCNU.
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PMID:Reduction of glutathione levels in livers of mice treated with N,N'-bis (2-chloroethyl)-N-nitrosourea. 45 78

The effects of several dietary supplements of antioxidants and enzyme inducers on ultraviolet light-mediated carcinogenesis were investigated. Glutathione (reduced) was without effect, but butylated hydroxytoluene, phenobarbital, and disulfiram all significantly suppressed the initiation and development of actinic lesions and tumors. On the basis of the present study and related previous ones, tumor inhibition appears to be due not to an umbrageous effect but rather to the induction of systemic physiological responses.
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PMID:Effects of dietary constituents on ultraviolet light-mediated carcinogenesis. 63 66

This prospective study was undertaken to substantiate observations that glutathione (GSH) inhibits or reverses tumor growth in humans with hepatocellular carcinoma (HCC), a neoplasm with an extremely poor prognosis. Eight patients with biopsy-proven HCC not amenable to surgery were given 5 g of GSH daily from the time of diagnosis. Two patients withdrew shortly after receiving GSH due to intolerable side-effects. Of the six eligible patients, two had mildly advanced tumors and four moderately advanced tumors. At 1-2-month intervals the liver was CT and ultra-sound scanned to assess the growth status of the tumor (progression, stagnation or regression). All the patients, except a male with a fibrolamellar type of HCC, died within 1 year after diagnosis. Two women with moderately advanced tumors survived almost 1 year, tumor growth stopped or regressed and in one of the women an initially abnormal alfa-1-fetoprotein (AFP) returned to normal after GSH treatment. AFP remained normal throughout the treatment period in the other women. These observations indicate that GSH may have a sex-dependent effect on HCC. However, further studies involving more patients are required to pursue this hypothesis.
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PMID:Glutathione treatment of hepatocellular carcinoma. 128 Mar 15

The oncosuppressive effect of melatonin on 9,10-dimethyl-1,2-benzanthracene (DMBA) induced rat mammary tumorigenesis led us to assess its possible modulatory influence on representative hepatic and mammary drug metabolizing enzymes in DMBA treated female Holtzman rats, reared in short and long photoperiods. Melatonin treated rats in either photoperiod showed a significant induction in hepatic and mammary levels of glutathione (GSH) and cytosolic activities of glutathione S-transferase (GST) when compared with the corresponding controls, along with a significant drop in hepatic microsomal contents of cytochromes b5 and P450. This induction of GSH and GST, and depletion of cytochromes b5 and P450 by melatonin may possibly be related to its anticarcinogenic potential in this tumor model.
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PMID:A possible modulatory influence of melatonin on representative phase I and II drug metabolizing enzymes in 9,10-dimethyl-1,2-benzanthracene induced rat mammary tumorigenesis. 128 33

Tumour levels of O6-alkylguanine-DNA-alkyltransferase (O6 AT) and glutathione content (GSH) were correlated with 1, 3-Bis (2-chloroethyl)-1-nitrosourea (BCNU) sensitivity in two human ovarian cancer xenografts (HOC8 and HOC18) and in two human glioblastoma xenografts (HG12 and HG15). HOC8 and HOC18, which were not responsive to BCNU treatment, showed O6 AT levels 14 and 23-fold higher than HG12 that was moderately sensitive to the same BCNU treatment. HG15, which was more sensitive to BCNU than HG12, showed significantly lower O6 AT levels. GSH levels were similar in all tumor xenografts. These data further stress the importance of O6 AT level as a relevant parameter for nitrosourea response in human tumours.
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PMID:Tumour levels of O6-alkylguanine-DNA-alkyltransferase and sensitivity to BCNU of human xenografts. 129 58

Chemotherapy failure remains a significant medical problem in the treatment of neoplastic disease and is thought to be due to many different factors including membrane transport, p-glycoprotein in multidrug resistance, glutathione and its related enzymes, topoisomerase II and DNA repair. Glutathione is a major constituent of non-protein thiol and participates in detoxification of chemotherapy and radiation. Thus, glutathione concentration is correlated with sensitivity to alkylating agents and radiation, and increased in resistant cell lines. Buthionine sulfoximine (BSO) is an inhibitor of glutathione biosynthesis and may increase cytotoxicities of alkylating agents, including melphalan and cisplatin, and radiation in sensitive and resistant cell lines. We studied effects on cellular glutathione levels and cytotoxicities of cisplatin, carboplatin and radiation by BSO treatment in human stomach cancer cell line (SNU-1) and ovarian cancer cell line (OVCAR-3). The results were as follow: 1) After BSO treatment of 1 mM and 2 mM for 2 days, the intracellular thiol concentration was depleted to 75.7% and 76.2% in SNU-1, and 74.1% and 63.0% in OVCAR-3, respectively. 2) The intracellular thiol concentration in SNU-1 was depleted to 33.4% after BSO 2 mM for only 2 hours incubation and 71.5% after small amount of BSO (0.02 mM) for 2 days. 3) The recovery of intracellular thiol concentration required more than 3 days after BSO removal. 4) BSO inhibited partially the growth of SNU-1 and OVCAR-3. 5) The cytotoxicities of cisplatin and carboplatin were markedly enhanced both in SNU-1 and OVCAR-3 by BSO treatment. 6) The cytotoxicities of radiation was increased in OVCAR-3 and SNU-1 by BSO treatment. Therefore, it is concluded that BSO can deplete effectively the intracellular thiol concentration and enhance the cytotoxicities of cisplatin, carboplatin and radiation.
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PMID:Effects of buthionine sulfoximine treatment on cellular glutathione levels and cytotoxicities of cisplatin, carboplatin and radiation in human stomach and ovarian cancer cell lines. 130 72

Glutathione S-transferases are involved in the detoxification of carcinogens and xenobiotics and are potentially associated with the development of drug-resistance. Forty-six testicular germ cell tumors and 33 adjacent normal testicular tissue specimens were analyzed at the RNA level for the expression of glutathione S-transferase alpha and pi. Glutathione S-transferase alpha was expressed in 31 of the 33 normal testicular tissues (94%) but in only three of the 46 germ cell tumors (7%). Glutathione S-transferase pi mRNA was detected in all normal and malignant testicular tissue samples. Thirteen testicular germ cell tumors and eight normal testicular tissue samples were analyzed at the protein level. The mean specific activity of total cytosolic glutathione S-transferase in tumor tissue was decreased by about 80% as compared to normal testicular tissue. Protein analysis of the glutathione S-transferase subunits of normal testicular tissue demonstrated the presence of the glutathione S-transferase classes alpha, mu and pi, with a predominance of the mu class. In testicular germ cell tumors the glutathione S-transferase subunit pattern showed a predominance of glutathione S-transferase pi representing 88% +/- 3% of total glutathione S-transferase. Since all three glutathione S-transferase isoenzyme classes contribute to the resistance to antineoplastic drugs, the altered glutathione S-transferase isoenzyme pattern and the decrease of glutathione S-transferase activity may play a role in the high inherent drug sensitivity of human testicular germ cell tumors.
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PMID:Glutathione S-transferases in human testicular germ cell tumors: changes of expression and activity. 131 14


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