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)

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.
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PMID:Establishment of drug resistance in human gastric and colon carcinoma xenograft lines. 190 5

In this report the effects of single doses of ionizing radiation on the mRNA expression of several proteins involved in multiple drug resistance were analyzed. Murine NIH 3T3 cells treated with single doses of 5, 10 and 20 Gy during the time interval from 1.5 to 72 h after irradiation were compared with their corresponding controls at the same points of time. The glutathione S-transferase-pi (GST pi) level was elevated in cells treated with 10 or 20 Gy from 24 to 72 h after irradiation compared with the control. Topoisomerase II alpha and thymidylate synthase were decreased in irradiated cells 24-72 h after exposure. These down-regulations were associated with cellular proliferation, determined by mRNA expression of the proliferation marker histone 3. Irradiated cells exhibited no alteration in the P-glycoprotein or glutathione peroxidase mRNA content. The finding that GST pi mRNA was overexpressed after irradiation was validated by investigations on a human lung carcinoma cell line (LXF 289) on the mRNA and protein level. Thus, our results indicate that irradiation alters the expression of proteins involved in multidrug resistance and may, therefore, play a role in clinical drug response.
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PMID:Effects of single doses of irradiation on the expression of resistance-related proteins in murine NIH 3T3 and human lung carcinoma cells. 755 53

In this report we analyzed the mRNA expression of the resistance-related enzymes DNA topoisomerase II (Topo II), thymidylate synthase (TS), glutathione S-transferase-pi (GST-pi) and glutathione peroxidase (GP) in childhood acute lymphoblastic leukemia (ALL) and their correlation to the proliferative activity, determined by Ki-67. RNA of blast cells from 54 children with untreated ALL were examined by dot blot hybridization. We found a significant positive correlation between Topo II and TS and cell proliferation. No significant correlation was detected between the mRNA expression of the glutathione-dependent enzymes GST-pi or GP and Ki-67. The results were substantiated by a semiquantitative RT-PCR-assay and by immunocytochemistry.
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PMID:Messenger RNA expression of resistance factors and their correlation to the proliferative activity in childhood acute lymphoblastic leukemia. 788 95

In the embryonal carcinoma cell line Tera and its 3.7-fold cis-diamminedichloroplatinum(II) (CDDP)-resistant subline, Tera-CP, parameters were studied that might have changed in relation to induction of CDDP resistance. Phenotypes of both lines were embryonal carcinoma. Karyotypes were related with a decreased mean number of chromosomes and fewer copies of the short arm of chromosome 12 in Tera-CP. Tera-CP showed cross-resistance for melphalan and 4-hydroperoxycyclophosphamide and had an 1.4-fold increased glutathione (GSH) level, a 1.5-fold increased glutathione S-transferase (GST) activity, and a 1.4-fold increased GST pi expression compared to Tera. Tera-CP was cross-resistant to 5-fluorouracil, but thymidylate synthase activity was not increased. Topoisomerase I and II activities and c-myc RNA and protein expression were the same in both lines. Platinum accumulation was equal in both lines, and platinum-DNA binding was lower in Tera-CP than in Tera. Both cell lines were xenografted into nude mice and tumors showed marked differentiation. Tera-CP tumors were 2.8-fold resistant to CDDP compared to Tera tumors. In new cell lines derived from xenografts of Tera and Tera-CP CDDP sensitivity, GST activity and GSH level corresponded with their sensitivity and resistant origin. Tera-CP is a model of in vitro and in vivo CDDP resistance with the GSH/GST detoxifying system as an important mechanism. CDDP resistance could be induced without a concomitant increase in differentiation.
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PMID:cis-diamminedichloroplatinum(ii) resistance in vitro and in vivo in human embryonal carcinoma cells. 824 27

Rectal carcinomas of previously untreated patients were analyzed for oxygen status using a computerized polarographic needle electrode histograph. Microvessel density and expression of c-jun, vascular endothelial growth factor (VEGF) and several resistance-related proteins (glutathione S-transferase-pi, GST; thymidylate synthase, TS; metallothioneine, MT) were determined using immunohistochemistry. To examine whether a relationship exists between intratumoral vessel density and tumor oxygenation, microvessel counts were determined in a 400x field using factor-VIII-related antigen and were correlated with the corresponding pO2 values. Linear regression analysis revealed a significant relationship between vessel density and oxygenation status of the tumors. Expression of c-jun, VEGF and resistance-related proteins was correlated with microvessel counts and pO2 values. Significantly lower vessel counts were found in GST- and MT-positive tumors and in tumors with overexpression of c-jun and VEGF than in negative tumors. In addition, significantly lower pO2 values were found in c-jun- and VEGF-positive tumors as well as a tendency for pO2 values to be lower in tumors where MT, GST and TS were expressed. These data show that expression of c-jun, VEGF, and resistance-related proteins is linked with poor vascularization and low oxygenation status in rectal cancer.
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PMID:Association of resistance-related protein expression with poor vascularization and low levels of oxygen in human rectal cancer. 869 May 19

Doxorubicin- (OAW-dox, SK-OV-dox), taxol- (OAW-tax, SK-OV-tax) and cisplatin- (SK-OV-cis) resistant cells derived from the parental OAW-42 and SK-OV-3 cell lines were established. OAW-42 sublines showed high resistance, the SK-OV-3 sublines only low resistance. OAW-42 sublines showed a cross-resistance profile typical of multidrug resistance (MDR). The sublines of SK-OV-3 showed a cross-resistance profile different from the OAW-42 sublines. The mRNA expression of several resistance proteins and related factors was analyzed. An overexpression of P-glycoprotein 170 (P-170), glutathione-S-transferase-pi (GST-pi), thymidylate synthase (TS), glutathione peroxidase (GP) and c-jun was found in OAW-dox and OAW-tax cells. Additionally, OAW-tax cells expressed a higher mRNA level of protein kinase Cbeta2. DNA analysis revealed a 2-fold gene amplification of P-170, whereas the genes for GST-pi, TS and GP were not amplified. SK-OV-dox and SK-OV-tax cells showed a decreased level of histone 3 (H3) and TS mRNA. This shows that the sublines of OAW-42 developed resistance by co-expression of several resistance-related proteins and proto-oncogenes whereas the sublines of SK-OV-3 expressed resistance by decreased expression of the proliferation-dependent proteins H3 and TS.
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PMID:Messenger RNA expression of resistance proteins and related factors in human ovarian carcinoma cell lines resistant to doxorubicin, taxol and cisplatin. 907 15

Resistance of tumor cells to chemotherapeutic drugs can not only be caused by treatment with antineoplastic agents but also by radiotherapy. The aim of this study was to analyze whether ionizing radiation can influence the mRNA expression of proteins which have been found to be involved in drug resistance of tumor cells. Human tumor cell lines (MCF-7, LXF and Sk-Mel) were treated with single doses of irradiation (5, 10 and 20 Gy). The expression of the resistance related proteins glutathione S-transferase-pi (GST-pi), topoisomerase II alpha (Topo II), thymidylate synthase (TS), O6-methylguanine-DNA-methyltransferase (MGMT), P-glycoprotein (Pgp), glutathione peroxidase (GPX) multidrug resistance-associated protein (MRP) and also of the heat-shock protein 70 (HSP 70) were determined at the mRNA level during the time interval from 1.5 to 72 h post-irradiation and compared with their corresponding controls. We also examined whether a relationship exists between these proteins and the proliferative activity (histone 3, Ki-67, statin) of the cells. We found that exposure of MCF-7, LXF and Sk-Mel cells to ionizing radiation increases the expression of the mRNA of GST-pi. Topo II, TS, HSP 70 and proliferation markers were also altered by exposure to ionizing radiation, but there was no common response of the three cell lines. No significant changes were observed in the expression of MGMT, Pgp, GPX and MRP after radiation treatment. Drug resistance tests revealed that irradiated MCF 7 cells were less sensitive to doxorubicin than non-irradiated control cells. Our results indicate that ionizing irradiation modifies the expression of some proteins involved in drug resistance and the response of MCF 7 cells to doxorubicin and may, therefore, play a role in clinical drug response.
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PMID:Messenger RNA expression of resistance factors in human tumor cell lines after single exposure to radiation. 941 87

The expression of the resistance-related proteins P-glycoprotein 170 (P-170), glutathione-S-transferase pi (GST-pi), topoisomerase II (Topo II), thymidylate synthase (TS) and metallothionein (MT) was investigated in leukemic cells of 19 children with newly diagnosed acute nonlymphoblastic leukemia. P-170 was expressed in 84%, GST-pi in 37%, TS in 47%, MT in 68%, and Topo II was downregulated in 37% of the cases investigated. No resistance factors were found in two patients, one positive factor was found in two patients, three factors in three patients, four factors in 7 patients, and all resistance factors investigated were present in one patient. Patients who developed a relapse expressed more than two resistance mechanisms significantly more often than patients who remained in remission (p = 0.005). The probability of continuous first remission was significantly lower where more than two resistance mechanisms were expressed. The results indicate that the higher the number of resistance-related proteins in childhood ANLL the poorer the prognosis of the patients.
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PMID:Multiple resistance mechanisms in acute nonlymphoblastic leukemia (ANLL). 961 93

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

Cross-resistance between different cytostatic agents which are structurally and functionally dissimilar is a common phenomenon called multidrug resistance (MDR). The best characterized mechanism of MDR involves P-glycoprotein. However, this does not completely explain MDR. Within the last few years, two new genes that can confer MDR have been identified (MRP and LRP). Furthermore, topoisomerase II has been associated with a special form of MDR. During the past several years, considerable interest has been shown in strategies to reverse MDR by using pharmacological compounds, monoclonal antibodies, immunotoxins, bispecific antibodies, antisense oligodeoxynucleotides, ribozymes, and albumin-conjugated drugs in in vitro and in vivo assays. All these experimental assays demonstrated that MDR can be circumvented. Two agents that have received the most attention in the clinic are verapamil and cyclosporin A. Despite some promising results (especially in hematological malignancies), the results obtained in the treatment of solid tumors with modulators have so far been quite disappointing. This may be explained by the fact that the MDR phenotype alone does not completely account for the resistance of human cancer. Several other resistance-related proteins (e.g., glutathione S-transferase, metallothionein, O6-alkylguanine-DNA-alkyltransferase, thymidylate synthase, dihydrofolate reductase, heat shock proteins) can be also expressed in resistant tumors. Additionally, cell proliferation, vascularization and apoptosis are involved in resistance.
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PMID:Multidrug resistance and its reversal. 971 85


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