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 have quantitated the levels of mRNAs in bone marrow samples from patients with multiple myeloma of the mdr1 gene (responsible for the Multidrug Resistance phenotype) and for two of the glutathione S-transferase gene, GST-2 and GST-3 (which can also inactivate a wide variety of cytotoxic drugs) and examined the relationship between the levels of expression of these genes and response to subsequent chemotherapy. From a total of 47 patients, 37 were treated with chemotherapy with 34 evaluable for response. Twenty-nine of the patients treated had not received any treatment prior to the marrow sampling while eight had previously received chemotherapy. Patients who failed to respond to initial chemotherapy had significantly higher levels of mdr1 than patients who responded (P = 0.01). In the total myeloma patient data set, mRNA levels for mdr1 and GST-2 were significantly correlated (Spearman rank correlation coefficient (r) = 0.54, P = 0.0004) as were expression levels of GST-2 with GST-3 (r = 0.43, P = 0.017). GST-3 and mdr1 levels were more weekly associated (r = 0.16, P = 0.4). These data would suggest a significant relationship between failure of chemotherapy in multiple myeloma patients and increases in expression of the mdr1 gene together with other genes whose products will generate additional mechanisms of resistance to chemotherapeutic agents.
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PMID:Levels of expression of the mdr1 gene and glutathione S-transferase genes 2 and 3 and response to chemotherapy in multiple myeloma. 134 25

The expression of the drug resistance markers P glycoprotein (P-170), glutathione S transferase-pi (GST-pi) and DNA topoisomerase II (Topo II) was analyzed in 16 human kidney carcinoma cell lines, 18 hematological malignancies, and 14 human breast carcinomas. We found a tendency for coexpression of increased P-170 and GST-pi and of increased P-170 and decreased Topo II expression in kidney carcinoma cell lines. A similar tendency was found between P-170 and GST-pi expression in breast carcinomas. In contrast, hematological malignancies did not show such a coexpression of resistance markers. Furthermore, we found interrelationships between the expression of resistance markers, resistance to doxorubicin or vincristine, and doubling times of kidney carcinoma cell lines. This indicates that the proliferative activity of tumor cells plays a role for the expression of resistance markers and the development of resistance to cytostatic drugs.
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PMID:Immunohistochemical detection of P glycoprotein, glutathione S transferase and DNA topoisomerase II in human tumors. 135 60

Ninety-four human non-small cell lung carcinomas (NSCLC) of previously untreated patients were analysed for the presence of P-glycoprotein (P-170) and glutathione S-transferase-pi (GST-pi) by means of immunohistochemistry. The expression of P-170 and GST-pi was compared with the results of doxorubicin resistance of the tumours in vitro and the smoking habits of the patients. A significant relationship between smoking habits of the patients and resistance of NSCLC was found (P = 0.007). Of the 72 tumours of smokers 57 (= 79%) were resistant, whereas of the 22 tumours of non-smokers only 11 (= 50%) showed resistance. Identical results were obtained when the analysis was restricted to patients with epidermoid lung carcinomas (P = 0.004). In contrast to these data, there exists no relationship between resistance and smoking for adenocarcinomas of the lung. Forty-two (= 58%) out of the 72 NSCLC of smokers expressed P-170, whereas out of 22 tumours of non-smokers only two tumours (= 9%) showed P-170 expression (P less than 0.0001). Similar results were obtained with epidermoid carcinomas (P = 0.004) and adenocarcinomas (P = 0.027). Fifty (= 69%) of 72 NSCLC of smokers revealed expression of GST-pi, whereas only nine (= 41%) of 22 tumours of non-smokers showed GST-pi expression (P = 0.015). Significant correlations also exist between resistance in vitro and expression of P-170 (P less than 0.0001) or expression of GST-pi (P less than 0.0001). Furthermore, a significant relationship between both proteins could be demonstrated (P less than 0.0001).
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PMID:Overexpression of P-glycoprotein and glutathione S-transferase-pi in resistant non-small cell lung carcinomas of smokers. 168 Mar 67

The relationship was analyzed between drug resistance and MDR1 (with MDR signifying multiple drug resistance) and glutathione S transferase-pi (GST-pi) gene expression in four stomach and four colon cancer cell lines. Northern blot analysis by pmdr1 probe showed that stomach cancer cell lines had no detectable level of MDR1 mRNA expression. By contrast, some levels of MDR1 mRNA expression were found in two colon cancer cell lines, indicating doxorubicin resistance. To examine the MDR1 mRNA in each cell level, in situ hybridization was used. It was found that all colon cell lines and two stomach cell lines had more silver grains per cell than KB cells (a human KB kidney epidermoid carcinoma cell line). However, the number of silver grains in each cell was heterogeneous in the colon and stomach cell lines. Low-level MDR1 mRNA expression could be detected even in cell lines without MDR1 mRNA expression by northern blot hybridization. These results suggest the possibility that all gastrointestinal cell lines can acquire multiple drug resistance. In addition, all examined gastrointestinal cell lines had high GST-pi mRNA expression. This GST-pi gene expression shows cisplatin resistance in the examined cell lines. Heterogeneity of GST-pi mRNA expression also was shown at the cellular level.
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PMID:Expression of MDR1 and glutathione S transferase-pi genes and chemosensitivities in human gastrointestinal cancer. 173 85

Increased expression of the mdr1 gene, encoding the 175 kDa P-glycoprotein, and the gst-pi gene, encoding the anionic isozyme of glutathione S-transferase (GST), have previously been detected in continuous human breast cancer cell lines selected in vitro for resistance to doxorubicin. In this present study we have measured RNA levels of mdr1 and gst-pi in primary human breast tumour biopsies prior to chemotherapy and from tumours which have different inherent responses to doxorubicin treatment, including colon, head and neck squamous cell carcinomas and myeloid leukaemias. Detectable levels of mdr1 mRNA was observed in 25 out of 49 breast tumours, with up to a 100-fold range in expression. A narrower range of gst-pi expression has also been observed in these tumours. Chemosensitivity of cells grown in short-term culture from some of the breast tumours has been measured by an in vitro colony forming assay in the presence of doxorubicin. Comparison of the dose of doxorubicin causing 50% inhibition of growth (ID50) with RNA levels showed that the tumours with high mdr1 expression had high ID50, while the more sensitive explants had low mdr1 expression. These results support a role for mdr1 gene expression in determining the response of human breast cancer cells to chemotherapy.
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PMID:Expression of mdr1 and gst-pi in human breast tumours: comparison to in vitro chemosensitivity. 197 Sep 34

The nucleotide sequence of the mdr1 gene encoding a putative drug efflux pump (P-glycoprotein) is homologous to a class of bacterial membrane-associated transport proteins. These bacterial proteins are part of a multicomponent system that includes soluble periplasmic proteins that bind substrates, channeling them through the membrane in an energy-dependent manner. We have investigated the possibility that a similar multicomponent transport system exists in a multidrug-resistant human MCF-7 breast cancer cell line that was initially selected for resistance to doxorubicin (AdrR MCF-7). AdrR MCF-7 cells overexpress both the mdr1 gene and the pi class isozyme of glutathione S-transferase (GST-pi) (EC 2.5.1.18). The latter is one of several isozymes known to have a ligand-binding function in addition to drug-metabolizing capabilities. Although we have recently shown that transfection of a functional GST-pi expression vector is insufficient to confer resistance to doxorubicin in cells that lack P-glycoprotein expression [Mol. Pharmacol. 36:22-28 (1989)], we examined the possibility that GST-pi interacts with P-glycoprotein to alter multidrug resistance. To do this, we have cloned cDNAs encoding these proteins from AdrR MCF-7 cells, constructed expression vectors containing these two genes, and transfected these vectors sequentially into drug-sensitive MCF-7 cells. The human mdr1 cDNA isolated from AdrR MCF-7 is a variant gene whose sequence differs from that isolated previously from vinblastine-resistant KB cells [Cell 53:519-529 (1989)], resulting in an amino acid substitution of alanine to serine at position 893 (mdr1/893ala). Transfection of eukaryotic expression vectors containing the mdr1 gene isolated from AdrR MCF-7 cells produced a multidrug-resistant phenotype in recipient cells, with a cross-resistance pattern similar to that in the AdrR MCF-7 cells. To determine whether GST-pi expression could augment resistance provided by mdr1, two clones transfected with mdr1, one with high levels (153% of mdr1 RNA in AdR MCF-7 cells) and one with low levels (10% of mdr1 RNA in AdrR MCF-7 cells), were subsequently cotransfected with a GST-pi expression vector and pSVNeo and selected for resistance to G418. Six of these clones contained levels of GST-pi that were 8- to 18-fold greater than GST levels found in mdr1-expressing clones transfected with nonspecific DNA. We found no difference in the degree of resistance to doxorubicin, actinomycin D, and vinblastine between the clones expressing mdr1 only and the clones expressing both mdr1 and GST-pi.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Multidrug resistance in cells transfected with human genes encoding a variant P-glycoprotein and glutathione S-transferase-pi. 197 72

After twenty years, understanding the mechanisms of tumor cells kill by anthracyclines still remains an active area of research. Of many mechanisms described for this class of drugs, efforts in the last year have focused on defining the role of free radical formation, topoisomerase II-induced DNA breakage, and P-170-dependent cellular accumulation of anthracyclines in tumor cell kill and resistance. First, in a number of tumor cell lines, the formation of free radical species from anthracyclines has been implicated in the cell killing. Modulation of detoxification pathways in a drug-resistant cell line e.g depletion of GSH, a substrate for peroxidase and transferase, enhanced both the formation of oxy-radicals and adriamycin cytotoxicity. It should be noted, however, that these findings are not true for every cell line examined, and free radical-mediated tumor kill may be cell- or tissue-specific. Second, anthracyclines-mediated topo II-dependent DNA cleavage was observed in most cell lines and reduced breaks were found in resistant cells. The decrease in single-strand breaks, however, neither correlated with the degree of resistance nor with differences in the relative topo II activity, which was in most cases only two-fold less in resistant cells than in sensitive cells. Finally, the reduced accumulation of the drug does not appear to be the only contributing factor in multidrug resistant cells and P-170 is not the only protein overexpressed in certain cells, e.g., an 85,000 Da protein may also be linked to adriamycin resistance. Although GST protein is overexpressed in most adriamycin resistant cells along with mdr1 gene, current evidence suggests that this protein may not be directly involved in adriamycin resistance. Taken together, both the mechanism of action and resistance to this class of drug likely vary among cell lines. Clinical studies in the past year have brought about interesting refinements in anthracycline-containing chemotherapy; ICRF-187 (by itself also cytotoxic) seems to offer protection against cardiac toxicity, while implicating iron in the mediation of cardiac damage. Out of a large number of newer anthracycline derivatives, clinical evidence indicates only a modest increase in therapeutic index with a few analogs, perhaps idarubicin and epirubicin. It is not yet clear that being able to receive more milligrams (or more cycles) of anthracycline eventually translates into a significantly better response rate or in a survival advantage. Much less clear is whether patients refractory to adriamycin may derive any benefit from newer anthracyclines.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Anthracyclines. 222 2

A melphalan-resistant human rhabdomyosarcoma xenograft, TE-671 MR, was established in athymic mice by serial melphalan treatment of the parent xenograft, TE-671, at the 10% lethal dosage (LD10); significant resistance was evident after ten passages of the tumor. TE-671 MR demonstrated a doubling time of 3.5 days and a latency period to 1000-mm3 tumors of 27.5 days. The glutathione level of TE-671 MR was 2.36 mumol/g tumor, wet weight, 2-fold higher than the parent line. The glutathione S-transferase activity of TE-671 MR was 117.8 mumol/min/mg protein, essentially unchanged from the parent line. Although TE-671 MR demonstrated cross-resistance to vincristine, dot blot analysis did not reveal an elevated expression of mdr1 mRNA in the resistant line. TE-671 MR demonstrated a 9.7-day growth delay following treatment with melphalan at the LD10 (compared to 20.9 days for the parent line). Treatment with L-buthionine-SR-sulfoximine (BSO) resulted in increased sensitivity to melphalan subsequently administered at 50% of the LD10 (melphalan alone, growth delays of 3.7 and 4.6 days in duplicate trials; melphalan plus BSO, growth delays of 7.2 and 9.8 days). Sensitivity to melphalan equal to that of the parent line TE-671 was not achieved, however. Treatment with BSO did not result in significantly enhanced sensitivity to subsequently administered vincristine (50% of the LD10) (vincristine alone, growth delays of 6.8 and 6.9 days in duplicate trials; vincristine plus BSO, growth delays of 10.9 and 7.5 days). These results suggest that generation of melphalan resistance may be associated with development of cross-resistance to vincristine; this resistance may be associated with (although not necessarily mediated by) glutathione elevation; this resistance may be partially overcome by BSO-mediated depletion of glutathione.
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PMID:Establishment of a melphalan-resistant rhabdomyosarcoma xenograft with cross-resistance to vincristine and enhanced sensitivity following buthionine sulfoximine-mediated glutathione depletion. 258 34

Increased expression of the glutathione S-transferase (GST; E.C.2.5.1.18) pi class isozyme is associated with both malignant transformation and drug resistance, as well as with decreased estrogen receptor content in breast cancer. In order to further characterize the role of this enzyme in drug resistance, we cloned the cDNA encoding the human isozyme GST pi and developed two eukaryotic expression vectors using this cDNA and either the human metallothionein IIa or cytomegalovirus immediate-early promoters. These GST pi expression vectors were cotransfected with pSV2neo into drug-sensitive MCF-7 human breast cancer cells, which have low amounts of GST activity and which do not express GST pi. The transfected cells were selected for G418 resistance and individual clones were screened for GST activity. Three clones that demonstrated increased GST activity were selected for further study. Immunoprecipitation studies demonstrated that the increase in GST activity in these clones was due to expression of GST pi. Although the total GST activity of the positive clones was increased as much as 15-fold over that in wild-type MCF-7 cells, there was no change in glutathione peroxidase activity, as measured using cumene hydroperoxide as a substrate. Immunoblot studies revealed that the increased GST enzyme produced in the transfected cells was identical in size to endogenous GST pi. Southern blot analysis demonstrated the incorporation of the GST pi expression vector into the genome of the positive clones and Northern blot analysis showed that the transfected genes made a hybrid GST pi RNA that was slightly larger than the endogenous GST pi RNA. Primer extension studies demonstrated that this increase in length corresponded to the added length of the 5' leader sequence of the expression vector. The effect of increased GST pi activity on the sensitivity of the transfected clones to several cytotoxic agents was assessed by colony-forming assay. The transfected clones were slightly more resistant (1.3-4.1-fold) to benzo(a)pyrene and its toxic metabolite benzo(a)pyrene-(anti)-7,8-dihydrodiol-9,10-epoxide, as well as to ethacrynic acid (3.1-to 4.4-fold). Although increased GST pi expression is found in MCF-7 cells selected for doxorubicin resistance, the transfected clones were not consistently more resistant to doxorubicin than control cells. In addition, the transfected cells were not resistant to either melphalan or (cis)-platinum, even though conjugation with glutathione is known to play a role in the detoxification of both of these drugs.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Elevation of pi class glutathione S-transferase activity in human breast cancer cells by transfection of the GST pi gene and its effect on sensitivity to toxins. 274 27

In the experiments, we examined the ability of a retroviral vector, pHaMASV, to encode two potential chemoprotective genes on separate transcription units. We previously described the pHaMSV vector, which includes the human MDR1 gene as a selectable marker and chemoprotective gene, plus an internal SV40 promoter for expressing a second heterologous gene along with MDR1 [M. E. Metz, D. M. Best, and S. E. Kane. Virology, 208: 634-643, 1995]. To test the ability of this vector to deliver two therapeutic genes simultaneously, the cDNA for human glutathione S-transferase pi (GST pi, the most abundant member of the glutathione S-transferase family in human tumor cells) was inserted into pHaMASV, and this plasmid was transfected into ecotropic packaging cells. The resulting pHaMASV.GST pi ecotropic retrovirus, which was produced at a titer of 2 x 10(6) colony-forming units/ml, was used to transduce NIH 3T3 cells. After initial selection in 60 ng/ml colchicine, a population of transduced cells was exposed to stepwise increasing colchicine concentrations to select for amplified expression of MDR1. As MDR1 expression increased, the expression of GST pi increased in concert, as demonstrated by Northern analysis, Western analysis, and measurement of glutathione S-transferase activity. Transduced cells growing in 1280 ng/ml colchicine had about 3-fold higher total glutathione S-transferase activity than nontransduced cells and 2.5-fold higher activity than transduced cells growing in 60 ng/ml colchicine. Northern hybridizations demonstrated a 3-5-fold increase in both the full-length retroviral message encoding MDR1 and the subgenomic mRNA encoding GST pi after amplification of resistance from 60 to 1280 ng/ml colchicine. The cytotoxic effects of several xenobiotics were evaluated in NIH 3T3 cells transfected with MDR1 (3T3.MDR) or transduced with the MDR1-GST pi retrovirus (3T3.GST640 or 3T3.GST1280) to evaluate the ability of our vector to produce a spectrum of drug resistances specific for the genes expressed. 3T3.MDR and 3T3.GST1280 cells expressing equivalent levels of MDR1 had identical levels of resistance to doxorubicin or colchicine. These results suggest that GST pi expression did not contribute to doxorubicin resistance in this model system. However, 3T3.GST640 cells were about 4-fold resistant to ethacrynic acid and 1-chloro-2,4-dinitrobenzene compared to cells expressing MDR1 alone, consistent with the ability of GST pi to conjugate both of these cytotoxins. Increases in drug resistance paralleled increases in gene-specific mRNA and recombinant protein levels in all cases.4+ chemotherapy.
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PMID:Transduction of NIH 3T3 cells with a retrovirus carrying both human MDR1 and glutathione S-transferase pi produces broad-range multidrug resistance. 766 83


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