Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Benzo[a]pyrene (BaP) is known to induce tumors in lung, forestomach, and skin in experimental animals. Earlier studies have suggested that glutathione S-transferase pi (GST pi) is involved in the detoxification of the "ultimate" carcinogenic metabolite of BaP, 7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE). The constitutive expression of GST pi in the liver of the male CD-1 mouse is higher than that of the female, and BHA has been shown to preferentially induce GST pi in the female as compared with the male mouse. The present studies were therefore designed to compare the susceptibility of male and female CD-1 mice to the carcinogenic effects of BaP and the protective effect of BHA. Results of these studies show that the female CD-1 mice are more susceptibile to the carcinogenic effect of BaP than the males and that the attenuation of BaP-induced carcinogenesis by BHA appears to be restricted only to the females.
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PMID:Differential carcinogenicity of benzo[a]pyrene in male and female CD-1 mouse lung. 926 22

Squamous cell carcinomas of the head and neck are a heterogeneous group of tumours with regard to anatomical site, natural history and response to various treatments. Assessment of the role of biomarkers as indicators of prognosis or response to treatment is thus complex. In the last decade, different biomarkers have been investigated in the search for objective and reproducible indicators of prognosis. In 69 squamous cell carcinomas of the oral cavity or oropharynx from patients treated with radical surgery alone, we determined cell kinetics, evaluated as in vitro 3H-thymidine labelling index (TLI), p53, bcl-2 and glutathione S-transferase pi (GST pi) expression, by using immunohistochemical methods. The biological variables were unrelated to one another or to established clinical and pathological prognostic factors. Univariate analysis showed that a low proliferative activity was associated to a significantly higher risk of death than that observed in patients with a high TLI, whereas p53, bcl-2 and GST pi expression did not provide prognostic information. Multivariate analysis showed that cell proliferation, gender and nodal status retained their clinical relevance. In the subset of node-negative patients, TLI and p53 expression were indicators of survival. Moreover, the combined analysis of TLI and p53 expression identified a subgroup of node-negative patients with slowly proliferating and highly p53-expressing tumours who died within 1 year of radical surgery. These results indicate that in patients with operable oral cavity and oropharyngeal cancer, biomarkers can provide important information on clinical outcome.
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PMID:Biological indicators of survival in patients treated by surgery for squamous cell carcinoma of the oral cavity and oropharynx. 950 24

We investigated the utility of examining biological markers to predict chemoresponse and survival. The subjects consisted of 39 unresectable gastric cancer patients treated with a combination of 5-fluorouracil and cis-platinum. The expression of p53, bcl-2, thymidylate synthase (TS), glutathione S-transferase pi (GST-pi), and vascular endothelial growth factor (VEGF) in the formalin-fixed biopsy samples of primary tumors before chemotherapy was examined immunohistochemically. The positive rate for VEGF, bcl-2, TS, p53, and GST-pi was 51, 10, 46, 38, and 69%, respectively. VEGF-positive cases showed a higher response rate than did negative cases (11 of 20 versus 2 of 19 cases; P = 0.0057). The cases that were negative for p53, TS, bcl-2, and GST-pi were more likely to respond to chemotherapy than the cases that were positive for these markers. The 10 cases having 4 or 5 favorable phenotypes (VEGF positive, p53 negative, bcl-2 negative, TS negative, and GST-pi negative) survived longer than the remaining 29 cases (P = 0.0069). Multivariate analysis revealed that the number of favorable phenotypes (> or = 4 versus < or = 3) had a greater impact on survival than performance status (0 versus 1 or 2), age (> 60 years versus < or = 60 years), macroscopic type (scirrhous versus nonscirrhous), histological type (intestinal versus diffuse), or tumor extent (locally advanced versus metastatic). Immunohistochemical examination of biological markers in biopsy samples may be useful in predicting the clinical outcome of unresectable gastric cancer patients treated with 5-fluorouracil and cis-platinum.
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PMID:Biological markers as a predictor for response and prognosis of unresectable gastric cancer patients treated with 5-fluorouracil and cis-platinum. 962 64

Pentachlorobenzene (PeCB) is an important environmental contaminant derived primarily from the by-product contamination of the popular fungicides hexachlorobenzene and pentachloronitrobenzene. Its tumor-promoting activity was studied in a medium-term initiation/promotion assay in male F344 rats. Animals were given a single i.p. injection of diethylnitrosamine (200 mg/kg body weight) and 2 weeks later were administered 0.1 or 0.4 mmol/kg per day PeCB by gavage in a corn oil vehicle, 7 days/week. At the end of week 3, rats were subjected to a partial hepatectomy. Results showed that PeCB, at both doses, significantly increased both the number and area of glutathione S-transferase pi (GST-P) foci (>0.2 mm diameter) (P < 0.05). This trend was dose-dependent. In addition to increases in preneoplastic foci, liver glutathione concentrations and glutathione-associated enzymes showed significant changes in animals treated with PeCB. Glutathione reductase (GR) and gamma-glutamylcysteine synthetase (gamma-GCS) were both significantly induced in the centrilobular region. Changes in oxidized glutathione concentrations corresponded with the increase in GR activity with decreases of 40 and 30% in the low and high dose groups, respectively. No significant changes were detected in reduced glutathione concentrations. Together with changes in GR and gamma-GCS expression, a decrease in GST-P foci around the central veins was significant (P = 0.004) at the high dose. In these animals, 26% of the foci were classified as centrilobular whereas 37 and 39% of the foci were centrilobular in the low dose and control groups, respectively. Because of the co-localized nature of the changes in glutathione-associated enzymes and the decreased incidence of centrilobular foci, our results suggest that the reduced cellular environment may ultimately play a role in negatively selecting for foci growth.
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PMID:Evidence for hepatocarcinogenic activity of pentachlorobenzene with intralobular variation in foci incidence. 980 69

Human glutathione S-transferase pi (GST-pi) may serve as a useful tumor marker because of the high frequency with which it is found in elevated levels in several tumor types. To determine whether GST-pi is useful as an indicator for cancers of the head and neck, expression of GST-pi mRNA was investigated by Northern analysis in this tumor type. Overexpression of GST-pi mRNA was detected in 9 of 36 (25%) primary head and neck squamous cell carcinomas (HNSCCs). When Southern blot analysis was used to examine the relationship between overexpression and amplification of the GST-pi gene, only 3 of 36 tumors (8%) showed GST-pi gene amplification. Thus, gene amplification is not critical to GST-pi mRNA overexpression in HNSCCs. Moderately and poorly differentiated HNSCCs tended to manifest elevated GST-pi mRNA compared with well differentiated tumors (30% for moderately and poorly differentiated tumors versus none of the well differentiated tumors examined). However, there was no significant correlation between GST-% mRNA overexpression and clinical stage, T stage (tumor size), N stage (neck nodal status), pathological nodes, or patient survival.
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PMID:Overexpression and amplification of glutathione S-transferase pi gene in head and neck squamous cell carcinomas. 981 45

We have established ten transplantable human soft-tissue sarcoma (STS) xenografts grown as subcutaneous tumours in the nude mouse. Nine xenografts originated from patients that needed chemotherapy in the course of their disease. The xenografts were tested for their sensitivity to maximum tolerated doses of five anti-cancer agents. Growth of treated tumours was expressed as a percentage of control tumour growth and a growth inhibition > 75% was measured for doxorubicin in 20% of the STS xenografts, for cyclophosphamide in 30%, for ifosfamide in 20%, for vincristine in 20%, whereas etoposide was not effective in the STS xenografts. In three out of ten STS xenografts MDR1 mRNA was detectable, but this was not related to the resistance against doxorubicin, vincristine or etoposide. Topoisomerase IIalpha mRNA expression levels did not reflect sensitivity to doxorubicin or etoposide. In all STS tissues, however, these levels were lower than topoisomerase IIalpha mRNA in a drug-sensitive human ovarian cancer xenograft. Glutathione concentrations and the activities of glutathione S-transferase, glutathione peroxidase and glutathione reductase were not related to resistance against the alkylating agents or doxorubicin. Of interest, in all STS tissues, glutathione S-transferase pi was the predominant isoenzyme present. In conclusion, chemosensitivity of the STS xenografts reflects clinical response rates in phase II trials on the same compounds in adult STS patients. Relatively low levels of topoisomerase IIalpha mRNA may partly account for intrinsic resistance against, for example, doxorubicin. Additional factors must contribute to moderate responsiveness to alkylating agents.
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PMID:Characterization of human soft-tissue sarcoma xenografts for use in secondary drug screening. 986 68

We induced tolerance to hexadecylphosphocholine (HePC) in the human epidermoid tumor cell line, KB. After 70 weeks of adaptation, the IC50 of HePC in the resistant cells KBr was 32-fold higher than in parental KB cells, and they were 30-fold more resistant to another ether lipid analogue, ET-18-OCH3. The KBr cells also showed cross-resistance to vincristine and colchicine while remaining sensitive to other chemotherapy agents. RT-PCR assays showed that expression of the multidrug resistance gene (MDR1) was positive in KBr cells, whereas the expression of GST-pi (glutathione S-transferase pi) and MRP (multidrug resistance protein) was undetectable in KBr cells. Both an immunocytochemistry test and Western blot analysis indicated that the expression of bcl-2 in KBr cells was strongly positive, while it was only mildly expressed in KB cells. Verapamil could not reverse the resistance of KBr to HePC although it is a well-known reversing agent against MDR1. Our results suggest that bcl-2 instead of MDR1 plays a major role in the resistance of KBr cells.
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PMID:Bcl-2 plays a key role instead of mdr1 in the resistance to hexadecylphosphocholine in human epidermoid tumor cell line KB. 1046 70

Neoadjuvant cisplatin-based chemotherapy has been widely used in the last decade for organ preservation or unresectable disease in advanced stage head and neck cancer. We examined the expression of a series of tumor markers that have been associated with chemotherapy resistance in pretreatment biopsies from 68 patients who received cisplatin-based neoadjuvant chemotherapy at either of two institutions. Patients received either cisplatin/5-fluorouracil (n = 49) or cisplatin/paclitaxel (n = 19). Expression of p53, glutathione S-transferase pi (GSTpi), thymidylate synthase (TS), c-erbB2, and multidrug resistance-associated protein was examined by immunohistochemistry. Expression of glutathione synthetase mRNA was measured by in situ hybridization. The overall response rate for cisplatin-based neoadjuvant treatment was 79%. The expression of several of the tumor markers was associated with resistance to neoadjuvant treatment, but none reached statistical significance. Overall survival (OS) was strongly correlated with the absence of p53 expression. The OS at 3 years was 81% in the p53-negative group, whereas it was 30% in the p53-positive group for patients treated with neoadjuvant chemotherapy (P < 0.0001). Expression of GST pi and TS was also significantly correlated with decreased OS after neoadjuvant treatment. At 3 years, the OS rate was 82% in the low GSTpi score group, compared to 46% in the high GSTpi score group (P = 0.0018). In the TS-negative group, the 3-year OS rate was 71% compared with 40% in the TS-positive group (P = 0.0071). We conclude that p53, GSTpi, and TS may be clinically important predictors of survival in patients receiving neoadjuvant chemotherapy for head and neck cancer.
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PMID:Prognostic value of p53, glutathione S-transferase pi, and thymidylate synthase for neoadjuvant cisplatin-based chemotherapy in head and neck cancer. 1063 46

Combined modalities are currently used for cancer therapy, although their mechanisms of activity remain incompletely deciphered. The design of new drug combinations suffers from our inability to anticipate accurately their efficacy or toxicity. They can be evaluated in vivo, using human tumors grafted into immunodeficient mice, as we did here with combined protocols used in the clinical setting. Xenografts of small cell lung carcinoma (SCLC) from eight patients were used to test the tumor sensitivity to etoposide (VP16; 12-16 mg/kg/days, days 1, 2, and 3), cisplatin (CDDP; 6-9 mg/kg/day, day 1) and ifosfamide (IFO; 90-210 mg/kg/day, days 1, 2, and 3) as single agents and to evaluate the efficacy of the two-drug or three-drug combinations. Five xenografts came from untreated patients (SCLC-61, SCLC-6, SCLC-10, SCLC-41, and SCLC-96) and three after treatment (SCLC-74, SCLC-101, and SCLC-108). p53 was inactivated in all of them. Tumor growth inhibition, growth delay, and the survival rate of tumor-bearing mice reflected individual SCLC chemosensitivity. As single agents, IFO inhibited tumor growth in a dose-dependent manner, whereas CDDP and VP16 had little or no effect. Both CDDP and IFO potentiated VP16, inducing complete regressions in the most sensitive SCLCs; VP16-IFO was more effective than VP16-CDDP, with complete regressions in six versus three of the eight tumors tested, respectively. CDDP-IFO was less effective than VP16-IFO, with three of eight SCLCs giving complete regressions. The three-drug combination led to modest improvement over the best two-drug combination but only for sensitive SCLCs. Because drug-responses distinguished two classes of SCLCs, as sensitive or refractory, MDR1, glutathione S-transferase pi, lung-related multidrug resistance protein, multidrug resistance protein, and topoisomerase IIalpha mRNA expression was studied by semiquantitative reverse transcription. There was no correlation with SCLC sensitivity; topoisomerase IIalpha and multidrug resistance protein was expressed in all cases, lung-related multidrug resistance protein and glutathione S-transferase pie in seven of eight, and MDR1 gene in four of eight. In conclusion, these SCLC xenografts displayed a pattern of chemotherapy response close to that observed in patients. This model confirmed that in two-drug combinations, each component potentiated the effects of the other, with VP16-IFO tending to be the best two-drug combination, both of which were more effective than VP16-CDDP and better tolerated than CDDP-IFO. The addition of a third agent gave a modest, if any, therapeutic benefit in the responders but none in refractory SCLCs. There was no correlation between the extent of response and resistance markers.
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PMID:Distinctive potentiating effects of cisplatin and/or ifosfamide combined with etoposide in human small cell lung carcinoma xenografts. 1081 35

Intracranial ependymomas are the third most common primary brain tumor in children. A variety of chemotherapy protocols have been introduced for the treatment of ependymoma although overall these have not contributed to patients outcome. To our knowledge, data on the prognostic value of immunoexpression of the chemoresistance-related proteins (ChRPs) in ependymomas are absent. Seventy-six patients with intracranial ependymomas who received combined treatment were studied retrospectively. Tumor specimens were immunohistochemically examined with antibodies to metallothioneins (MT), glutathione S-transferase pi (GST pi) and P-glycoprotein (P-GP). The results demonstrated significant preponderance of expression of all the above-mentioned ChRPs for the low-grade tumors. The progression-free survival time was found to be significantly shorter for immunonegative tumors in both tumor grades. Multivariate analysis using a Cox hazard model revealed that recurrence-free survival time is significantly associated with tumor grade, and MT and P-GP expression. Risk of recurrence increased for the high-grade ependymomas (hazard ratio 2.85; P = 0.004), and decreased for the MT-positive tumors (hazard ratio -2.72; P = 0.005) and for the P-GP-positive tumors (hazard ratio -2.02; P = 0.02). The obtained results allow one to conclude that ChRPs expression is closely associated with low-grade ependymomas and immunohistochemical findings may be estimated as a predictor for local tumor progression.
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PMID:Prognostic value of immunoexpression of the chemoresistance-related proteins in ependymomas: an analysis of 76 cases. 1084 92


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