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)

Phenotypically distinct but genetically identical obese mottled yellow Avy/a and lean pseudoagouti Avy/a sibling mice and their congeneic black a/a littermates provide an experimental system for distinguishing phenotypic effects from genotypic effects in the expression of the genotype at the organismic level. Hepatic glutathione S-transferase activity in obese yellow Avy/a (YS X VY) F-1 hybrid female mice was only about 66% of that found in their lean black a/a sisters. This decreased enzyme activity was not a direct effect of the Avy/a genotype but was associated with the obesity of the yellow mice since the enzyme activity in lean pseudoagouti Avy/a female siblings was similar to that found in the black a/a mice. Long-term feeding of 160 ppm lindane in the diet decreased the enzyme activity in all phenotypes but did not eliminate the difference between the obese yellow and lean pseudoagouti and black mice. Interpretation of the available data suggests that no direct relationship exists between the level of hepatic glutathione S-transferase activity and the enhancement of tumor formation in yellow Avy/a mice. Several inbred mouse strains and F-1 hybrids were also screened for this enzyme activity. No strain differences were found but sex differences within different inbred strains were not uniform. In the AE and YS strains and their F-1 hybrid enzyme activity was higher in female than in males. In contrast, BALB/c and VY strain males had higher enzyme activity than the corresponding females.
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PMID:Hepatic glutathione S-transferase activity in mice: effects of Avy/-genotype, obesity, lindane treatment, and sex. 241 15

Many structurally unrelated nonmutagenic peroxisome proliferators induce altered areas, neoplastic nodules, and hepatocellular carcinomas in rats. Unlike the lesions induced by genotoxic hepatocarcinogens, these lesions do not stain positively for the phenotypic markers gamma-glutamyl transpeptidase (GGT) and glutathione-S-transferase P (GST-P). To ascertain whether the absence of immunocytochemically detectable GST-P and GGT proteins in peroxisome proliferator-induced neoplastic lesions is due to the absence of specific mRNAs, we analyzed the total RNA isolated from hepatocellular carcinomas induced by three different peroxisome proliferators (ciprofibrate, Wy-14643, and BR-931) and the genotoxic carcinogens, 2-acetylaminofluorene and aflatoxin B1 (AFB), for the presence of GST-P, GGT, and alpha-fetoprotein (AFP) mRNAs. Northern and dot blot analysis of total RNA isolated from liver tumors induced by three different peroxisome proliferators revealed no detectable GST-P, GGT, and AFP mRNAs. GST-P mRNA was also not detected in a transplantable hepatocellular carcinoma established from a liver tumor induced by ciprofibrate. In contrast, GST-P mRNA levels were high in primary liver tumors induced by both 2-acetylaminofluorene and AFB and the two transplantable hepatocellular carcinomas established from such tumors. By immunoblot method, GST-P protein was found to be abundant in both primary and transplantable liver tumors induced by genotoxic carcinogens but not in those derived from peroxisome proliferator treatment. The GGT and AFP mRNAs were also not found in all 18 liver tumors induced by peroxisome proliferators that were analyzed and also in the ciprofibrate-derived transplantable liver tumor. The expression of GGT and AFP genes in liver tumors induced by 2-acetylaminofluorene and AFB was variable. These studies with peroxisome proliferators show that the GST-P and GGT gene derepression is not essential for the hepatocarcinogenesis or successful tumor transplantation. Further characterization of the molecular basis for the differential expression, particularly of the GST-P gene in liver tumors, may help identification of the critical event(s) in hepatocarcinogenesis by genotoxic carcinogens and nongenotoxic peroxisome proliferators.
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PMID:Lack of expression of glutathione-S-transferase P, gamma-glutamyl transpeptidase, and alpha-fetoprotein messenger RNAs in liver tumors induced by peroxisome proliferators. 245 33

By sequential use of GSH-affinity chromatography and chromatofocusing, the isoenzymes of glutathione transferase from tumor and non-tumor kidney tissues have been purified and their properties compared. On the basis of electrophoretic mobilities on SDS/polyacrylamide gel, substrate specificities toward the diagnostic substrates cumene hydroperoxide and ethacrynic acid and immunoreactivity with antisera raised against alpha, mu and pi class glutathione transferases, it was found that most of the isoenzymes purified from both tumor and non-tumor kidney can be identified as members of either alpha or pi classes. All the samples investigated lacked mu class glutathione transferase. In addition, we could identify in tumor samples two transferases GST-7.6 and GST-5.8/5.9 which on the basis of immunological properties cannot be related to any of the members of the three major classes of glutathione transferases. The latter do not appear to have corresponding forms in non-tumor tissues. It was suggested that specific transferases can be selectively expressed by tumor kidney carcinoma.
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PMID:Electrophoretic and immunological analysis of glutathione transferase isoenzymes of human kidney carcinoma. 249 96

The content of glutathione S-transferase placental form (GST-pi) in colon and esophageal cancer tissues was determined by single radial immunodiffusion or activity inhibition tests. Average levels in colon adenomas and carcinomas were 163 +/- 38 and 143 +/- 30 micrograms/g, respectively, about 6-fold higher than the value of 25 +/- 4 micrograms/g observed for normal colonic mucosa. The content in esophageal cancer was similarly increased at 240 +/- 160 micrograms/g, about 6-fold higher than the level found in normal mucosa, 42 +/- 21 micrograms/g. The content was significantly higher in highly differentiated carcinoma (331 +/- 138 micrograms/g) than in moderately (205 +/- 123) or poorly (125 +/- 61) differentiated carcinomas, suggesting that GST-pi content seems to be related to the degree of differentiation of esophageal cancer. GST-pi was also expressed in cell lines derived from various cancers, including IMR 32, TE-9, and Ca Ski cells. The results thus indicate that GST-pi may be a useful marker for a wide range of cancers. An enzyme-linked immunosorbent assay developed to determine serum GST-pi content is described. Using this method GST-pi could be accurately measured in the range between 0.7 and 150 ng/ml, without interference of other isoenzymes. The serum GST-pi content was 1.3 +/- 1.2 ng/ml in 35 healthy controls and values of over 3.7 ng/ml (control mean + 2 SD) were found in patients with cancers of the stomach (10 of 23 cases), esophagus (26/43), bile duct (3/9), and colon (3/9), and in some leukemic cases. Although elevation of the serum content was not so often as that of tissue content, the fact that higher serum values of patients with esophageal cancer often reverted to the normal range after surgical removal of the cancer suggested a direct derivation of serum GST-pi from tumor tissues. Thus, follow-up of elevated serum GST-pi levels may be useful for monitoring cancer patients during the course of treatment.
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PMID:Elevation of the placental glutathione S-transferase form (GST-pi) in tumor tissues and the levels in sera of patients with cancer. 250 86

Tannic acid inhibits the mutagenicity of several polycyclic aromatic hydrocarbons (PAHs) and their bay-region diol-epoxides. Our prior studies have shown that when applied topically to Sencar mice, tannic acid caused substantial inhibition of epidermal PAH metabolism, subsequent PAH-DNA adduct formation, and PAH-induced skin tumorigenesis (H. Mukhtar et al., Cancer Res., 48:2361-2365, 1988, and references therein). In this study the effects of tannic acid supplementation in the diet (1%, w/w, in AIN-76 diet) of Sencar mice on benzo(a)pyrene (BP) metabolism and its subsequent DNA binding and tumorigenesis in lung and forestomach were evaluated. Animals receiving a tannic acid-containing diet showed diminished aryl hydrocarbon hydroxylase and 7-ethoxy-resorufin O-deethylase activities in the forestomach and lung. Elevated glutathione S-transferase and NAD(P)H:quinone reductase activities were observed in these tissues. Maximum effects occurred after 45 days of feeding. Administration of [3H]BP p.o. to animals resulted in lower covalent binding to DNA in forestomach and lung of animals receiving tannic acid-containing diet as compared to animals receiving AIN-76 control diet. Tumor induction studies in forestomach and lung revealed significant protection against BP-induced tumorigenesis in animals fed tannic acid-supplemented diet as compared to animals fed control diet. The mice fed tannic acid-supplemented diet developed 3.3 forestomach tumors/mouse compared to 5.2 tumors/mouse in animals receiving control diet. The numbers of pulmonary tumors per mouse in animals fed tannic acid-supplemented diet and control diet were 1.6 and 3.1, respectively. Topical application of 7,12-dimethylbenz(a)anthracene to animals fed tannic acid-supplemented diet did not result in significant protection against skin tumorigenesis. However, a slight delay in the onset of skin tumor formation occurred in tannic acid-fed animals when compared to animals receiving control diet. Our data suggest that dietary supplementation with tannic acid affords protection against BP-induced forestomach and lung tumorigenesis in rodents.
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PMID:Effect of dietary tannic acid on epidermal, lung, and forestomach polycyclic aromatic hydrocarbon metabolism and tumorigenicity in Sencar mice. 250 36

Recent evidence supports the concept that Adriamycin cytotoxicity may be mediated by drug semiquinone free radical and oxyradical generation. We tested this hypothesis further by exposing drug-sensitive (WT) and 500-fold Adriamycin-resistant MCF-7 human breast tumor cells (ADRR) to exogenous superoxide- and hydrogen peroxide-generating systems and subsequently monitored cell proliferation as a measure of cytotoxicity. The ADRR tumor cells tolerated a 4-fold greater exposure than sensitive cells to superoxide generated by the xanthine/xanthine oxidase system. Likewise, exposure to hydrogen peroxide produced by the action of glucose oxidase on glucose revealed a 4-fold diminished susceptibility of the drug-resistant cells to this reduced form of oxygen. Similar results were obtained by the direct application of hydrogen peroxide to cells. For both cell lines, cytotoxicity was dependent upon the magnitude and the duration of reactive oxygen exposure. When WT and ADRR cells were cultured under hyperoxia (95% O2:5% CO2), in order to stimulate the intracellular production of oxyradicals, proliferation was inhibited to a greater extent in the drug-sensitive cell line. Additionally, hyperoxia potentiated the cytotoxicity of Adriamycin to both sensitive and drug-resistant cells, but the effect depended upon the concentration of the drug. Under hyperoxic conditions, Adriamycin caused oxygen radical-dependent cytotoxicity to the WT tumor cells at clinically relevant drug concentrations as low as 2 to 3 nM. With ADRR tumor cells, hyperoxia increased the cytotoxicity of Adriamycin at concentrations above 5 microM. Paradoxically, both the WT and the ADRR tumor cells were equally susceptible to the cytotoxic effects of gamma irradiation. It is known that the Adriamycin-resistant MCF-7 cells greatly overexpress glutathione peroxidase and glutathione transferase activities; however, other biochemical defenses against reactive drug intermediates and oxygen radicals have been reported to be similar in the two cell lines. We have reexamined those observations in this report. The resistance of ADRR breast tumor cells to Adriamycin appears to be associated with a developed tolerance to superoxide, most likely because of a twofold increase in superoxide dismutase activity, and a decreased susceptibility to hydrogen peroxide, most likely because of 12-fold augmented selenium-dependent glutathione peroxidase activity. Acting in concert, these two enzymes would decrease the formation of hydroxyl radical from reduced molecular oxygen intermediates.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential oxygen radical susceptibility of adriamycin-sensitive and -resistant MCF-7 human breast tumor cells. 253 95

Generation and enhanced detoxification of toxic free radicals by glutathione peroxidase and glutathione transferase in human breast tumor cells have been suggested to play an important role in toxicity and in resistance to adriamycin. We have examined the biochemical basis of paraquat-induced free radical formation and the mechanism of resistance to this agent in human breast tumor cell lines. We have also compared the similarities and differences between adriamycin and paraquat in their mode of free radical formation and tumor cell kill. Anaerobic incubation of paraquat resulted in the formation of the paraquat cation radical in both the sensitive and resistant cells which increased with time and was enhanced by NADPH addition. Our studies show that while both adriamycin and paraquat form hydroxyl radicals (.OH) in these cell lines, adriamycin was 2-3 fold better at reducing oxygen. The formation of .OH was inhibited by exogenously added superoxide dismutase and catalase, indicating the involvement of both superoxide anion radical and hydrogen peroxide. In the adriamycin-resistant cell line, less .OH was formed by each of these drugs. While the .OH appeared to be formed outside by both adriamycin and paraquat in the drug-sensitive cells, experiments using chromium oxalate as a spin-broadening agent suggest that the drug-induced .OH formation in the resistant cells is an intracellular event. The adriamycin-resistant cell line was also cross-resistant to paraquat, suggesting a common mechanism of toxicity for both drugs. However, adriamycin was significantly more toxic (4000-times) to the sensitive cells suggesting that either other mechanisms or site-specific free radical formation are also important in biochemical mechanisms of adriamycin toxicity.
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PMID:Resistance of paraquat and adriamycin in human breast tumor cells: role of free radical formation. 253 56

Mechanisms for resistance were studied in three classic type, human small cell lung cancer cell lines, GLC14, GLC16, and GLC19, that were established from one patient during clinical follow-up. Clinically the tumor changed from sensitive (GLC14) to completely resistant to (chemo)therapy (GLC19) during this period. The stain with JSB-1 antibody, detecting the Mr 170,000 multidrug resistance associated glycoprotein, was most pronounced in GLC16 and absent in GLC19. Intracellular Adriamycin (Adr) concentrations were decreased in GLC16 and GLC19 versus GLC14. Glutathione levels were 12.9, 15.5, and 16.6 micrograms/mg protein; total sulfhydryl groups were 36.5, 45.7, and 48.8 micrograms/mg protein; and glutathione S-transferase activity was 13, 29, and 43 nmol I-chloro-2,4-dinitrobenzene/min/mg protein for GLC14, GLC16, and GLC19, respectively. Incubation with DL-buthionine-S,R-sulfoximine increased Adr and cisplatin induced cytotoxicity, whereas X-ray induced cytotoxicity remained the same. Catalase activity increased from 0.88 to 1.73 to 3.83 mumol H2O2/min/mg protein in, respectively, GLC14, GLC16, and GLC19. Compared to GLC14 and GLC16, Adr induced a higher amount of DNA strand breaks in GLC19. In none of the three cell lines could Adr induced DNA strand breaks be repaired. X-ray induced a comparable amount of DNA strand breaks in all three cell lines but all cell lines were capable of repairing the X-ray induced DNA strand breaks within 90 min. It is concluded that a number of different mechanisms are operative and that some but not all of the observed changes in mechanisms for drug resistance in these lines correlate with the clinical data.
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PMID:Resistance mechanisms in three human small cell lung cancer cell lines established from one patient during clinical follow-up. 254 37

A rat liver gap junction (GJ) cDNA probe that detects mRNA encoding the 32 Kd GJ-protein (connexin 32) was employed to study GJ-protein gene expression in rat liver tumors induced by a single exposure to diethylnitrosamine (DEN) followed by exposure to 2-acetylaminofluorene (AAF)/CCl4/AAF or induced by systemic administration of N-ethyl-N-hydroxyethylnitrosamine (EHEN). All carcinomas generated by these carcinogens showed markedly reduced levels of GJ-protein mRNA. This may indicate that GJ-protein levels and gap-junctional intercellular communication (GJIC) capacity are also severely compromised. Moreover, all hyperplastic nodules also showed a reduced level of GJ-protein mRNA. Taken together with our earlier finding that the liver tumor promoter phenobarbital inhibits GJ-protein gene expression, these results suggest that deranged GJIC is a relatively early event in liver multistage carcinogenesis. A range of other cDNA probes was also used to characterize gene expression in the DEN-induced tumors. Induction of expression was seen for glutathione S-transferase (placental form) (GST-P), gamma-glutamyltranspeptidase (GGT), and c-raf but not for c-Ha-ras or c-myc.
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PMID:Changes in gap junction protein (connexin 32) gene expression during rat liver carcinogenesis. 255 87

The reversible stage of tumor promotion, which follows the stage of initiation and precedes that of progression in multistage carcinogenesis, is a unique example of reversible toxicity in biological systems. In order to study the molecular mechanisms involved in the action of promoting agents during this stage, the regulation of the expression of genes for two enzymes of glutathione metabolism, gamma-glutamyl transpeptidase (GGT) and the placental isozyme of glutathione S-transferase (GST-P), was studied under several different conditions of promotion during multistage hepatocarcinogenesis in the rat. Promotion by phenobarbital caused an increased expression of both of these genes in altered hepatic focal lesions, although this was somewhat more variable in the case of the GGT gene. C.I. Solvent Yellow 14, an industrial dye, served as an effective promoting agent. Feeding this dye resulted in a dramatic increase in the expression of GST-P, but not that of GGT in altered hepatic foci. Factors in crude, cereal-based diets inhibited the stage of promotion by diethylnitrosamine, but enhanced promotion by phenobarbital in a synergistic manner. In contrast, at least one purified diet had the converse effect during this stage. The mRNA levels of GST-P were uniformly elevated dramatically in reversible nodules and neoplasms of rat liver that had been induced by diethylnitrosamine and phenobarbital promotion. In contrast, the level of GGT mRNA was somewhat variable, with an occasional neoplasm exhibiting almost a background level of expression of this gene. Therefore, the altered regulation of multiple genes in hepatocytes during the stage of promotion can vary with the promoting agent itself; this process may be related to the heterogeneous gene expression seen in hepatic neoplasms. A possible role for specific DNA sequences in the 5' flanking regions of such genes is considered. In addition, a cDNA clone to the mRNA of human liver GGT was isolated and sequenced. The homology of the coding sequence of the human liver GGT mRNA to that of rat kidney GGT mRNA was striking.
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PMID:Regulation of the expression of some genes for enzymes of glutathione metabolism in hepatotoxicity and hepatocarcinogenesis. 256 99


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