Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Estimating the risk of human cancer associated with exposure to methylene chloride. 182 Jul 33

Cancer development is a long-term multistep process which allows interventional measure before the clinical disease emerges. The detection of natural substances which can block the process of carcinogenesis is as important as the identification of anti-tumoral drugs since they might be used in chemoprevention of cancer in high-risk groups. In vivo rodent models of chemical carcinogenesis have been used to study plant-derived inhibitors of carcinogenesis such as indoles, coumarins, isothiocyanates, flavones, phenols and allyl-sulfides. Since the standard in vivo rodent bioassay is prolonged and expensive, shorter reliable protocols are needed. Two in vivo medium-term protocols for evaluation of modifiers of carcinogenesis are presented, one related to liver and the other to bladder cancer. Both protocols use rats, last 8 and 36 weeks and are based on the two-step concept of carcinogenesis: initiation and promotion. The protocols use respectively the development of altered foci of hepatocytes expressing immunohistochemically the placental form of glutathione S-transferase and the appearance of pre-neoplastic urothelium and papillomas as the "end-points". The use of these protocols for detection of plant-derived inhibitors of carcinogenesis appear warranted.
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PMID:Medium-term protocols for in vivo evaluation of chemical modifiers of carcinogenesis. 184 12

The aim of the present study was to analyse in invasive carcinomas of the uterine cervix, the anionic glutathione S transferase (GST pi) gene, possibly implicated in the drug resistance of human cancers. Total RNA preparations obtained from invasive cervical cancers (106 specimens), carcinomas in situ (CIS) (three specimens) and normal cervical epitheliums (24 specimens) were analysed by Northern and slot blot hybridisation. A 0.7 kb GST pi transcript band was detected in all the cervical specimens. GST pi mRNA levels were lower in normal cervix (mean: 0.7 +/- 0.1 arbitrary units) than in invasive carcinomas (mean: 2.5 +/- 1.5 units) (Student test P less than 10(-4)). However no significant difference was observed between invasive cancers of advanced stages (III and IV) and those of early stages (I and II). The presence of human papillomavirus in cancers and in normal cervices did not influence significantly the GST pi mRNA level. Neither amplification nor gross rearrangement of GST pi gene could be observed after Southern blot analysis of genomic DNA. In conclusion, our data indicate that the presence of high levels of GST pi transcripts in invasive cancers may be a consequence of the multiple biochemical changes which accompany cervical carcinogenesis.
Br J Cancer 1991 Feb
PMID:Expression of anionic glutathione S transferase (GST pi) gene in carcinomas of the uterine cervix and in normal cervices. 184 44

Medullary thyroid carcinoma (MTC) is a cancer that is relatively insensitive to clinical chemotherapy. Our previous studies have demonstrated that an established human MTC cell line, TT, seems to possess an intrinsic resistance phenotype when tested for its chemosensitivity to multiple antineoplastic agents. We now report our investigation on the potential mechanisms responsible for the chemoresistance of TT cells. Northern analysis showed an increased level of multidrug resistance gene (mdrl) mRNA in TT and in an inherently drug-resistant colon carcinoma cell line, LoVo, when compared with CEM, a drug-sensitive leukemic lymphoblastic cell line; the latter two cell lines were included here as a control. Verapamil (10 microM) partially reversed resistance to doxorubicin in TT and LoVo cells, but had no effect on doxorubicin cytotoxicity to CEM cells. Expression of glutathione-S-transferase-pi (GST pi) gene was undetectable in TT, whereas, under similar conditions, GST pi mRNA was detectable in LoVo. Growth kinetics studies revealed that doubling times of the 3 cell lines in exponential growth were 95, 37, and 24 h for TT, LoVo and CEM, respectively. Flow-cytometric analysis showed that the percentage of TT population is S phase was 49% and 33% of the LoVo and CEM cell populations, respectively, while the G1/G0 fraction of TT was about 63% and 61% higher than that of LoVo and CEM, respectively. Our data suggest that the intrinsic chemoresistance in TT cells may be attributed to the combined factors of overexpression of the mdrl gene, a slower growth rate and a smaller proliferation fraction, although other factors or mechanisms that are yet to be investigated may also act in concert to contribute to the resistance phenotype of TT.
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PMID:Intrinsic drug resistance in a human medullary thyroid carcinoma cell line: association with overexpression of mdrl gene and low proliferation fraction. 188 39

Following EMS mutagenesis, three estramustine (EM) resistant DU 145 human prostatic carcinoma cell lines were clonally selected by exposure to incrementally increasing concentrations of the drug. Although only low levels of resistance (approximately 3-fold) were attainable, this resistance was stable in the absence of continuous drug exposure. These EM-resistant clones (EMR 4,9,12) did not exhibit cross resistance to vinblastine, taxol, or adriamycin, and had collateral sensitivity to cytochalasin B. None of the lines had elevated expression of P-glycoprotein mRNA or glutathione S-transferase activity, suggesting a phenotype distinct from the classic multi-drug resistance phenotype. This conclusion was supported further by the observation that two MDR cell lines (FLC mouse erythroleukaemic and SKOV3 human ovarian carcinoma cells) showed sensitivity to EM. Fluorescent activated cell sorting analysis of the effects of EM on cell cycle traverse revealed that at EM concentrations up to 20 microM an increasing percentage of wild type cells were blocked in G2/M; no such effect occurred in EMR lines. Differential interference contrast microscopy was employed to study EM's effect on mitosis. EMR lines were able to form functional, albeit smaller, spindles at EM concentrations that resulted in chromosomal disorganisation and inhibition of mitotic progression in wild type cells. EMR lines were able to progress through mitosis and cytokinesis at the same rate as untreated cells. Tritiated EM was used to evaluate potential drug uptake/efflux mutations in ERM clones. EMR 4 and 9 incorporate less EM than wild type cells; however, they have significantly decreased cellular volumes. The initial efflux rate constants for EMR clones were greater than for wild type cells. Within 5 min greater than 70% of the drug was lost from resistant cells compared to a 50% loss by the wild type. Although the specific mechanisms of resistance have yet to be defined, the lack of collateral resistance to other MDR/anti-microtubule agents could serve as the basis for the clinical use of EM in combination chemotherapy.
Br J Cancer 1991 Aug
PMID:Resistance to the antimitotic drug estramustine is distinct from the multidrug resistant phenotype. 189 55

Effects of age on the induction of glutathione S-transferase placental form (GST-P)-positive hepatic foci in rats were examined using a medium-term liver bioassay system (for carcinogens). F344 male rats aged 6, 26 and 46 weeks were initially given a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg) and, beginning 2 weeks later, received 0.02% 2-acetylaminofluorene (2-AAF), 0.05% phenobarbital (PB) or 1.3% acetaminophen (AAP) in the diet for 6 weeks. All animals were subjected to two-thirds hepatectomy 3 weeks after the DEN injection and were killed at week 8. Quantitative analysis of GST-P-positive foci revealed significantly (P less than 0.001) increased induction over control levels in terms of both numbers and areas for 2-AAF at all ages (6, 26 and 46 weeks), but especially in the 6-week-old case. In the PB- and AAP-treated groups, the respective enhancing and inhibitory influences were most pronounced in the animals aged 6 weeks, and were less marked in older rats. Thus, the response of F344 rats to the modifying effects of chemicals was age-dependent, the conclusion being drawn that young rats are more susceptible and therefore more appropriate for assessment of carcinogenic, promoting and inhibitory effects of chemicals.
Jpn J Cancer Res 1991 Mar
PMID:Age-dependent induction of preneoplastic liver cell foci by 2-acetylaminofluorene, phenobarbital and acetaminophen in F344 rats initially treated with diethylnitrosamine. 190 51

Marked alterations of hepatic drug-metabolizing enzymes were observed in hepatitis- and hepatoma-predisposed rats (LEC rats) fed a choline-deficient diet. The diet enhanced the development of hepatitis with severe jaundice. The levels of two major classes of cytochrome P-450, P-450PB and P-450MC, were markedly decreased. GST-Yp was dramatically increased, whereas GST-Ya, Yb1 and Yb2 were decreased. LEA rats (the control rats to LEC) fed a choline-deficient diet mimicked LEC rats fed a normal diet in terms of the above enzyme alterations, indicating that hypomethylation is involved in the pathogenesis of hepatitis and hepatoma in LEC rats. Such hypomethylation may initiate the hepatocytes that spontaneously develop hepatitis and hepatoma.
Jpn J Cancer Res 1991 Apr
PMID:Enhancing effect of a choline-deficient diet on alterations of hepatic drug-metabolizing enzymes in hepatitis- and hepatoma-predisposed rats (LEC rats). 190 19

We established multidrug-resistant human gastric and colon xenograft lines by means of intratumoral injections of four agents, doxorubicin (DXR), cisplatin (CDDP), 5-fluorouracil (5-FU) and mitomycin C (MMC), into subcutaneous SC1NU and SW480 tumors once a week or less. Such intermittent drug exposure is commonly used in clinical chemotherapeutic protocols. All xenograft lines acquired resistance to the injected drugs as evaluated by in vivo drug-resistance tests. Many of the drug-resistant lines showed various patterns of cross resistance to other drugs. In order to analyze the mechanism of resistance in vivo, we investigated the expression of drug resistance gene, which has been extensively studied in vitro. We used four complementary DNAs (cDNAs) for multidrug resistance (MDR1), glutathione S-transferase-pi (GST-pi), thymidylate synthase (TS) and dehydrofolate reductase (DHFR), as probes. We observed GST-pi, DHFR and TS mRNA expression at various levels, but MDR1 mRNA expression was found only in SW480/DXR by the method of poly (A+) RNA selection. Four resistant SW480 lines had higher TS mRNA expressions. Six resistant lines had stronger GST-pi mRNA expression. Five resistant lines had higher DHFR mRNA expression. Drug resistance genes related to the treated drug were also expressed in this in vivo model; MDR1 in SW480/DXR, GST-pi in SW480/CDDP and in SC1NU/CDDP and TS in SW480/5-FU. In contrast to in vitro resistant lines which have been reported as models of drug resistance, the expression of drug resistance genes in vivo was not always correlated to the acquisition of cross resistance. These resistant xenograft lines and the methods developed to induce drug resistance in vivo should be useful for studies on the mechanism of drug resistance in the clinical setting.
Jpn J Cancer Res 1991 May
PMID:Establishment of drug resistance in human gastric and colon carcinoma xenograft lines. 190 5

Modifying potentials of various chemicals on tumor development were investigated in a wide-spectrum organ carcinogenesis model using male F344/DuCrj rats. The animals were treated with N-nitrosodiethylamine (100 mg/kg body weight, ip, single injection at the commencement of the study), N-methyl-N-nitrosourea (20 mg/kg body weight, ip, 4 times during weeks 1 and 2) and N-bis(2-hydroxypropyl)nitrosamine (0.1% in drinking water, during weeks 3 and 4) for multi-organ initiation and then were given one of 14 test chemicals including 6 hepatocarcinogens, 7 non-hepatocarcinogens and 1 non-carcinogen, or basal diet for 16 weeks. All rats were killed at the end of week 20, and the major organs were carefully examined for preneoplastic and neoplastic lesions. Immunohistochemical demonstration of glutathione S-transferase-positive foci was also used for quantitative assessment of liver preneoplastic lesion development. Modifying effects were shown for 11 out of 14 test agents in the liver, forestomach, glandular stomach, lung, urinary bladder or thyroid, 7 of them targeting more than two organs. This was the first demonstration to our knowledge that clofibrate possesses enhancing potential for urinary bladder carcinogenesis and an inhibiting effect on thyroid carcinogenesis. Caprolactam showed no effect in any organ, in agreement with its established inactivity. The results indicated that the system could be reliably applied as a medium-term multiple organ bioassay for assessment of the modification potential of test agents in unknown target sites.
Jpn J Cancer Res 1991 Jun
PMID:Modifying effects of various chemicals on preneoplastic and neoplastic lesion development in a wide-spectrum organ carcinogenesis model using F344 rats. 190 50

The effects of epidermal growth factor (EGF) (10 ng/ml) and insulin (100 nM) on the expression of glutathione S-transferases (GSTs), especially the GST-P form (GST 7-7), were examined in primary cultured rat hepatocytes in serum-free medium. On culture with EGF and insulin, the GST activities towards 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene were transiently decreased on day 2 to 10% of those of freshly isolated hepatocytes and then increased to 60 to 100% of those of freshly isolated cells on day 4. Western blot analysis of GSTs revealed that GST-P, which is not present in freshly isolated hepatocytes, was markedly induced and that GST subunits 3 and 4 of the Mu class also increased after addition of EGF and/or insulin, while the subunits 1 and 2 of the Alpha class disappeared. Northern blot analysis showed that on addition of EGF and insulin the level of GST-P mRNA was also elevated and expressions of the nuclear oncogenes c-jun and c-fos were enhanced. These results suggest that the enhanced expression of GST-P induced by EGF or insulin in primary cultured rat hepatocytes might be regulated by JUN and FOS proteins.
Jpn J Cancer Res 1991 Jul
PMID:Induction of glutathione S-transferase P-form in primary cultured rat hepatocytes by epidermal growth factor and insulin. 190 48


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