Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Four independent antibodies (6A, 5F, 2H and 2F) to Glutathione S-transferase pi (GST-pi) were selected to characterize their epitopes. Amino acid analysis of 5.6 K and 7.4 K tryptic peptides appeared to suggest that the epitope recognized by antibodies 2H and 2F is located in the N-terminal 44 peptides of GST-pi, and that of 6A and 5F is located in the C-terminal 69 peptides. Reactivities of antibodies 6A and 5F with two synthetic peptides indicated that 6A recognized an epitope in the C-terminal hydrophilic fragment 176Leu-209Gln, and could be distinguished from 5F which recognized an epitope in the 141Thr-176Leu hydrophobic fragment. The differential immuno-reactivity of antibodies 6A and 5F with GST-pi itself, was characterized by the particularly high reactivity of 6A and almost no reactivity of 5F with the natural conformation of GST-pi in solution. This may be explained by differences in the hydropathic natures of their epitopes. The 6A antibody was useful for immunodetection of GST-pi in circulation, while 5F was found to be most suitable for histochemical staining of tumor tissue.
 ...
PMID:Determination of antigenic epitopes recognized by four monoclonal antibodies to glutathione S-transferase pi (GST-pi). 169 59

The phenotypic response of rat liver to a carcinogenic protocol involving initiation/selection and promotion with and without phenobarbital (PB) feeding was studied in pubertal and adult male rats. Considering the early presence of preneoplastic nodular areas, it appeared that pubertal rats, initiated at 6-7 weeks, presented a higher susceptibility to the protocol than adult rats initiated at 9-10 weeks. Altered liver phenotype was characterized by: (1) gamma-glutamyl-transpeptidase (GGT) and glutathione S-transferase (GST) activities; (2) the expression of two forms of cytochrome P-450; de novo PB-inducible P-450 II B 1,2 and P-450 II C 7 normally expressed in 45-day-old rats and PB-inducible, and (3) the expression of albumin and alpha-fetoprotein cDNAs. In the absence of PB, the susceptibility of pubertal rat liver to hepatocarcinogenesis was related to a special metabolic phenotype enriched in GGT and GST activities by comparison with the quasi-normal expression of both P-450s. Adult rat liver presented a less altered pattern closer to that of noninitiated rat liver. During PB promotion, the loss of PB inducibility of P-450 II C 7 in pubertal rat liver suggested that the hormonal status of the animals could interact with initiation to modulate specific gene expression. The late phase of PB promotion revealed the loss of highly differentiated functions (P-450s, albumin), whereas enzymatic markers associated with preneoplastic foci showed a persistent high expression.
Tumour Biol 1990
PMID:Effect of rat developmental stage at initiation on the expression of biochemical markers during liver tumor promotion. 170 Aug 61

The expression of immunoreactive glutathione S-transferase (GST) was examined in hepatic neoplasms induced in rainbow trout by aflatoxin B1 (AFB) or 1,2-dimethylbenzanthracene (DMBA). Tumors were induced in adult trout by continuous dietary exposure to 8 p.p.b. AFB1 for 12 months or embryo bath exposure to DMBA (5 p.p.m. for 24 h, 3 times with 12 h intervals between exposures). Polyclonal antiserum specific for the two major trout hepatic GST subunits in trout liver was produced by immunizing rabbits with affinity-purified trout GST. Hepatocellular, cholangiolar and mixed neoplasms as well as foci of hepatocellular alteration were examined for GST immunoreactivity by the PAP technique. The majority of lesions were GST-deficient (AFB treated, 67%; DMBA treated, 54%), whereas GST expression was induced in 21% (AFB treated) and 31% (DMBA treated) of altered hepatic foci. The GST-induced foci were consistently small (AFB treated, 0.07 +/- 0.05 mm2; DMBA treated, 0.02 +/- 0.01 mm2) and none had progressed beyond the altered focus stage. The majority of larger advanced lesions (adenomas and carcinomas) were GST deficient (AFB treated, 2.33 +/- 0.35 mm2; DMBA treated, 2.95 +/- 0.59 mm2). These studies demonstrate that induced GST expression occurs in some small populations of hepatocytes, but not in larger advanced stages of malignant progression of aflatoxin- or PAH-induced hepatic neoplasms in rainbow trout.
 ...
PMID:Expression of immunoreactive glutathione S-transferases in hepatic neoplasms induced by aflatoxin B1 or 1,2-dimethylbenzanthracene in rainbow trout (Oncorhynchus mykiss). 170 71

Inducibility of oxidative stress in rat liver in vivo by menadione-associated redox cycling activation under redox enzyme modulating conditions was examined by monitoring hepatocyte injury and 8-hydroxydeoxyguanosine (8-OHdG) levels of liver DNA. In addition, the treatment-associated liver tumor initiating activity was assessed in terms of development of gamma-glutamyl-transpeptidase (GGT)- and glutathione S-transferase placental form (GST-P)-positive foci and hyperplastic nodules. With or without following menadione treatment (50 mg/kg, i.g.), redox enzyme modulations of increased cytochrome P450 reductase activity induced by phenobarbital (PB)-Na (100 mg/kg, i.p. for 5 days), inhibition of DT-diaphorase by dicumarol (25 mg/kg, i.p.) and depletion of glutathione by phorone (200 mg/kg, i.p.), with or without further supplement of iron EDTA-Na-Fe(III) (70 mg/kg, i.p.), caused both substantial hepatocyte necrosis and 8-OHdG production in Fischer 344 male rats. Subsequent feeding with a 0.05% PB diet for 64 weeks resulted in slightly increased development of GGT-positive foci but not GST-P positive lesions or hyperplastic nodules, suggesting a lack of tumor-initiating activity of the oxidative DNA damage associated with redox enzyme modulations with or without menadione.
 ...
PMID:Induction of 8-hydroxydeoxyguanosine but not initiation of carcinogenesis by redox enzyme modulations with or without menadione in rat liver. 170 52

Malignant melanoma tumors are inherently resistant to anticancer drugs, yet the mechanism of this resistance is not understood. B16 melanoma, a spontaneous tumor which arose in the C57BL/6 mouse; BL6 melanoma, a highly invasive variant; and Mel-ab melanocytes, isolated from C57BL/6 mouse skin, were examined for intracellular glutathione (GSH) content. GSH was higher in BL6 and B16 cells than in Mel-ab cells, with the highest concentration in BL6 cells. Since GSH is thought to be involved in the resistance of many cells, including melanoma, to cytotoxic drugs, we determined whether intracellular GSH content was altered during transformation of Mel-ab cells. After transfection with pHO6T1 plasmid DNA, containing an activated c-H-ras oncogene flanked by transcriptional enhancers, 1.3% of successfully transfected Mel-ab melanocytes formed distinct colonies in soft agar, compared to 0.2% of cells transfected with control pHO6 plasmid without H-ras. Approximately 53% of the pHO6T1-transfected colonies isolated from soft agar grew in 5% CO2 in the absence of phorbol-12-myristate-13-acetate, a requirement for the extended growth of Mel-ab cells. Cells transfected with control pHO6 plasmid and non-transfected Mel-ab cells did not survive under these conditions. All of the isolated pHO6T1 transfected cells formed tumors when inoculated into C57BL/6 mice. Transformed cells had higher GSH content than non-transfected Mel-ab cells, whether expressed on a cellular or cell volume basis. Although the amount of oxidized glutathione was greater in the tumorigenic cells, this could not account for the overall increase in GSH. Neither glutathione S-transferase nor gamma-glutamyl transpeptidase activities were increased in the H-ras-transfected cells. Northern blot analysis confirmed H-ras-specific RNA in pHO6T1-transformed cells.
 ...
PMID:Induction of glutathione content in murine melanocytes after transformation with c-H-ras oncogene. 171 78

The effect of betel leaf extract and some of its constituents, eugenol, hydroxychavicol, beta-carotene and alpha-tocopherol, on benzo[a]pyrene-induced forestomach neoplasia in male Swiss mice was examined. Betel leaf and its constituents decreased the number of papillomas per animal with the maximum protection, considering molar dosage, exhibited by beta-carotene and alpha-tocopherol. Except for beta-carotene, eugenol, hydroxychavicol and alpha-tocopherol increased the levels of reduced glutathione in the liver while glutathione S-transferase activity was enhanced by all except eugenol. Of seven sources, Banarasi betel leaves showed the maximum amounts of beta-carotene and alpha-tocopherol.
 ...
PMID:Chemopreventive efficacy of a betel leaf extract against benzo[a]pyrene-induced forestomach tumors in mice. 179 25

The lung is a target organ for the toxic effects of several chemical agents, including natural products, industrial chemicals, pesticides, environmental agents, and occasionally, drugs. Factors that establish the lung as a target organ include selective tissue exposure, high tissue oxygenation, and the presence of bioactivating systems that can generate toxic products from initially innocuous substances. Selective pulmonary exposure most often results from the fact that the lung serves as the major portal of entry for most airborne substances, but in some cases, selective exposure is the consequence of accumulation of agents, such as certain basic amines, from the circulation. Lung tumor development following long-term exposure to cigarette smoke or diesel engine exhaust is an example of pulmonary toxicity resulting from selective external exposure. Selective internal exposure, on the other hand, is exemplified by the pulmonary uptake of the herbicide paraquat from the circulation which is in part responsible for its lung-toxic effects. Although the lung contains drug metabolizing enzymes similar to those found in the liver, the enzymatic systems in the lung are sometimes highly concentrated in specific cell types. In the rabbit, for example, the lung-selective toxicity of the natural product ipomeanol is the consequence of relatively large amounts of cytochromes P450 2B1 and 4B1 in nonciliated bronchiolar epithelial cells (Clara cells) of the terminal airways. These P450 enzymes are highly proficient in vitro at converting ipomeanol to reactive products. Lung tissue contains other enzymic systems which are capable of catalyzing phase I biostransformation pathways (e.g., flavin-containing amine monooxygenase, amine oxidase, and prostaglandin synthase). Examples, however, where pulmonary metabolism by these pathways results in lung toxicity are less numerous than with P450 mediated reactions. Pulmonary prostaglandin H-synthase mediated cooxygenation has been shown to activate procarcinogens such as benzo(a)pyrene 7,8-dihydrodiol, aflatoxin B1, and monosubstituted hydrazines. The activities of pulmonary phase II (conjugation) pathways may also contribute to lung toxicity. Low glutathione transferase activity (relative to P450 mediated aryl hydrocarbon hydroxylase activity) in lung tissue has been suggested to correlate with elevated risk of lung cancer in smokers. Other examples of lung-specific toxic agents and possible causative roles of biotransformation are also discussed.
 ...
PMID:The role of metabolism in chemical-induced pulmonary toxicity. 181 90

Dichloromethane (methylene chloride, CH2Cl2) has been shown to significantly increase the incidence of malignant lung and liver tumors in B6C3F1 mice inhaling high concentrations of CH2Cl2 vapor for the majority of their natural lifetime. CH2Cl2 is extensively metabolized in mammalian species through two competing pathways: (1) oxidation by the mixed function oxidase enzymes, and (2) conjugation with glutathione catalyzed by glutathione-S-transferase(s)(GST). Since elevated tumor incidences have not been observed in B6C3F1 mice exposed to 1,1,1-trichloroethane, a halogenated solvent with similar physical-chemical properties (but only minor amounts of mammalian metabolism), it appeared that biologically reactive intermediates (BRIs) from one or both of the pathways of CH2Cl2 metabolism were involved in the tumorigenic process. Development of an integrated pharmacokinetic model incorporating quantitative measures of mammalian physiology, chemical solubility, and metabolic rate constants permitted formulation of a plausible hypothesis for the tumorigenic effects of CH2Cl2: namely that BRIs formed by the CH2Cl2/GST(s) may react with critical molecules in the target organs. This hypothesis is consistent with the dose-dependency, route-dependency, and species-specificity of CH2Cl2 for the induction of lung and liver tumors. Based on this hypothesis as well as in vivo and in vitro measurements of CH2Cl2 metabolism in humans, it was possible to prepare quantitative estimates of the cancer risk in human populations. Examination of these risk estimates indicates that development of quantitative procedures for describing the production of BRI in target tissues may cause significant changes in the levels of estimated risk.
 ...
PMID:Estimating the risk of human cancer associated with exposure to methylene chloride. 182 Jul 33

High levels of intracellular glutathione (GSH) may result in resistance of tumor cells to cytotoxic drugs. Because of the innate refractory nature of melanoma cells to chemotherapy, we have used a syngeneic murine system consisting of nontumorigenic Mel-ab melanocytes, tumorigenic H-ras-transformed melanocytes (C9.1), and the highly metastatic BL6 melanoma cells to examine the GSH content, glutathione S-transferase (GST) activity, and sensitivity to buthionine sulfoximine (BSO) and other cytotoxic drugs. Compared to the nontumorigenic melanocytes, both C9.1 and BL6 melanoma cells have nearly fivefold higher GSH content, and BL6 cells have increased GST activity. C9.1 and BL6 cells are more resistant to the cytotoxic effects of BCNU and adriamycin; however, the degrees of resistance do not reflect the increased GSH content in these cells. Pretreatment of BL6 melanoma cells with 50 microM BSO depleted over 90% of their GSH content and enhanced the growth-inhibitory effects of L-dopa methylester, BCNU, bleomycin, and dacarbazine. Exposure to BSO alone was not toxic to the tumor cells for up to 24 hr, but was significantly cytotoxic in the melanocytes after 9 hr. The sensitivity of these cells to BSO appears to depend on a critical level of GSH depletion which is not related to the initial GSH content. These studies suggest that the resistance of melanoma cells to cytotoxic drugs is only partially attributed to changes in the GSH system caused during cellular transformation.
 ...
PMID:Differential sensitivities of murine melanocytes and melanoma cells to buthionine sulfoximine and anticancer drugs. 182 27

The SV40 T antigen (T)/adenovirus E1A-binding domain of the retinoblastoma gene product (pRB) has been fused to S. japonicum glutathione S-transferase, and the chimera, bound to insoluble glutathione, was used to search for cellular proteins that can interact specifically with pRB. At least seven such proteins were detected in extracts of multiple human tumor cell lines. These proteins failed to bind to a family of pRB fusion proteins that harbor inactivating mutations in the T/E1A-binding domain and to the wild-type fusion protein in the presence of a peptide replica of the pRB-binding domain of T. Therefore, the binding of one or more of these proteins may contribute to the growth-suppressing function of pRB.
 ...
PMID:Identification of cellular proteins that can interact specifically with the T/E1A-binding region of the retinoblastoma gene product. 182 28


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>