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:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Advanced breast cancer responds to a range of cytotoxic agents, but resistance always develops. Understanding the mechanisms of resistance may provide new therapeutic options. There are several major groups of resistance mechanisms. 1) The multidrug resistant phenotype. This is due to a membrane pump that can extrude a wide range of anticancer drugs--the P-glycoprotein. It is inhibited by a range of clinically used calcium channel blockers such as nifedipine and verapamil. Several other membrane proteins of 180 KD, 170 KD, 300 KD and 85 KD have been reported and are associated with MDR. 2) Glutathione transferences and detoxification mechanisms. These are a multigene family of enzymes that conjugate glutathione to chemically reactive groups. There are 3 major groups of enzymes--acidic, basic and neutral. They have been implicated in resistance to doxorubicin, melphalan cisplatinum chlorambucil and other alkylating agents. Other protecting systems include metallothionein and selenium dependent glutathione peroxidase. HSP27 confers doxorubicin resistance. 3) Topoisomerase II. DNA topoisomerases are involved in several aspects of DNA metabolism in particular genetic recombination, DNA transcription, chromosome segregation. They are a target for doxorubicin, mitoxantrone, VP16. Low levels of expression are associated with resistance. However, it is oestrogen inducible and this may be of therapeutic value. A novel topo IIb which is more drug resistant has been reported. 4) DNA repair. A score or more of genes are involved in the repair of DNA damage by drugs and radiation. Defective DNA repair may predispose to cancer of the breast and be responsible for adverse radiation reactions. Enhanced repair has been shown to be a mechanism of cisplatinum resistance. Several genes are inducible by DNA damage and may confer resistance e.g. A45. 5) Drug activation. Mitomycin C as well as cyclophosphamide and VP16 require activation for their effects. Low levels of cytochrome p450 reductase are associated with MMC resistance.
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PMID:Mechanisms of multidrug resistance in cancer treatment. 135 55

This study has provided evidence that exposure of the wild-type MCF-7 human breast carcinoma cell line to the mutagen ethyl methane sulphonate (EMS), followed by selection in vincristine (VCR), resulted in a stably-resistant subline, designated VCREMS, which expressed an approximately 14-fold level of resistance to VCR. This VCREMS subline showed cross-resistance (3-fold) to adriamycin (ADR) and to etoposide (3-fold), but not to cisplatin. The addition of a non-toxic concentration of verapamil (6.6 microM) significantly enhanced VCR cytotoxicity only in the resistant subline. This resistance was associated with over-expression of P-glycoprotein (Pgp), but without a concomitant increase in Pgp mRNA or gene amplification. In addition, activities of total glutathione S-transferases (GST) and glutathione peroxidase were elevated in this resistant subline, with over-expression of the GST-pi isozyme and its associated mRNA being identified, without gene amplification. This VCR-selected resistant MCF-7 cell line therefore provides another example of a breast carcinoma subline in which there is co-ordinate over-expression of both Pgp and GST-pi, without attributing a causal relationship to either event, and extends the range of anti-tumour drugs known to elicit modifications in glutathione metabolism.
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PMID:Over-expression of P-glycoprotein and glutathione S-transferase pi in MCF-7 cells selected for vincristine resistance in vitro. 135 56

Drug resistance is a major problem in cancer chemotherapy. Treatment protocols generally include a number of different cytotoxic drugs given in combination. Therefore, drug resistance in the tumor is likely to result from the coexpression of several cellular activities able to prevent cell killing by any of the drugs used. In this study we have measured several potential drug resistance mechanisms consisting of the multidrug resistance gene product P-glycoprotein, glutathione, glutathione-transferase and -peroxidase, and the DNA repair enzyme O6-alkylguanine-DNA-alkyltransferase in samples of colon carcinoma and normal adjacent mucosa from 23 untreated patients. All of these, with the exception of P-glycoprotein, showed significant increases in tumor tissue levels when compared with normal tissue from the same patient. The significance was highest for glutathione peroxidase (P less than or equal to 0.0005). Individual patients, however, showed very different patterns, with none, several, or all monitored resistance mechanisms elevated in the tumor. The implications both in the choice of drugs and in the use of resistance modifying agents to improve therapy for the individual patient are discussed.
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PMID:Assessment of P-glycoprotein, glutathione-based detoxifying enzymes and O6-alkylguanine-DNA alkyltransferase as potential indicators of constitutive drug resistance in human colorectal tumors. 167 23

Four human colon cancer cell lines (SW620, LS 180, DLD-I, and HCT-15) and sub-lines isolated in vitro by selection with Adriamycin were studied for reversal of intrinsic and acquired Adriamycin resistance, using buthionine sulfoximine (BSO) to deplete cellular glutathione alone and in combination with the P-glycoprotein antagonist verapamil. GSH levels varied among the parental cell lines but did not increase with resistance. In the parental SW620, DLD-I and HCT-15 and their drug-resistant derivatives, there was no relation between the effect of the glutathione-depleting agent BSO, the mRNA expression of both selenium-dependent glutathione peroxidase (GPx) and glutathione S-transferase pi (GST pi), bulk glutathione S-transferase (GST) activity, and the degree of resistance. However, in LS 180 and its derivative sub-lines, which do not principally rely on P-glycoprotein (Pgp) for Adriamycin resistance, treatment with BSO demonstrated a relatively diminished GSH depletion and enhanced recovery. In comparison with the other acquired cell lines, BSO specifically reversed acquired resistance in the LS 180 Adriamycin-resistant subline (LS 180 Ad150) after short-term drug exposure. Furthermore, the LS 180 Ad150 cells demonstrated an increase in both GPx and GST pi mRNA expression. These observations suggest that glutathione-mediated detoxification of Adriamycin may play a role in the resistance of this sub-line. Verapamil enhanced Adriamycin cytotoxicity 1.2- to 12-fold in the intrinsically resistant cells and as much as 15-fold in cell lines with acquired resistance. Combination of BSO with verapamil resulted in additive, but not synergistic, reversal of resistance. The results underscore the complex nature of Adriamycin resistance, and suggest a role for drug-resistance-modulating agents in the treatment of colon carcinoma.
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PMID:Contribution of glutathione and glutathione-dependent enzymes in the reversal of adriamycin resistance in colon carcinoma cell lines. 168 79

A B16 melanoma line was repeatedly transplanted subcutaneously in C57BL/6 mice. On day 4 after every transplant, the animals were treated with doxorubicin (DXR), 10 mg/kg i.p. The aim of the work was to develop an in-vivo model of resistance to the antiblastic in order to analyze some possible mechanistic aspects of the process in the course of time. After 16 transplants and treatments the melanoma completely lost its sensitivity to the antiproliferative effects of maximal tolerated doses of DXR and showed over-expression of P-glycoprotein. Compared to the parental line, the in vitro resistance index was 4.6. After 27 transplants and treatments the melanoma did not increase its in vitro resistance to DXR further, and this resistance was completely reversed by verapamil. The behavior of the antioxidant defenses (superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase, glutathione reductase and glutathione) was evaluated after 4, 16 and 27 transplants and treatments with DXR. At no stage did the treated melanoma show any variation in the antioxidant enzymes. Compared to the parental counterpart its glutathione levels were elevated after four treatments (+80%), when, however, the line was still sensitive to the in vivo effects of DXR, and after 16 treatments (+30%). Instead, no variation of the glutathione content was seen after 27 treatments with DXR. These results seem to exclude the possibility that the antioxidant defenses play a major role in the resistance of this B16 melanoma line to DXR. On the other hand, the low but, however, 'clinically' significant resistance of the tumor to the antiblastic seems mainly related to the mechanisms linked to the P-glycoprotein over-expression.
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PMID:Antioxidant defenses in a B16 melanoma line resistant to doxorubicin: an in vivo study. 168 13

Several mechanisms of drug resistance have been defined using cell lines selected for resistance in vitro. However, the relevance of these to tumor cell resistance in vivo remains unclear. We established tumor cell lines from biopsies of human sarcomas before and after doxorubicin therapy. One pretreatment sarcoma line, STSAR90, was 6-fold less sensitive to doxorubicin than was a normal fibroblast line, AG1522. The sensitivities of six other sarcoma lines were similar to that of AG1522. STSAR90 cells did not overexpress P-glycoprotein mRNA, by Northern analysis with the pCHP1 complementary DNA fragment. Photoaffinity labeling with the vinblastine analogue N-(p-azido-3-125I-salicyl)-N'-beta-aminoethylvindesine did not show increased P-glycoprotein concentrations. Accumulation of [3H]daunomycin was not decreased in STSAR90 compared with a less resistant sarcoma line, STSAR11, nor was the doxorubicin sensitivity of STSAR90 increased by coincubation with verapamil. Glutathione levels were twice as high in STSAR90 as in STSAR11, and glutathione peroxidase activity was 3.5- to 6-fold higher. This was due mostly to an increase in selenium-dependent peroxidase activity. After exposure to doxorubicin, STSAR90 cells formed only half as much measurable hydroxyl radical as STSAR11, as detected by electron spin resonance spectrometry. Doxorubicin sensitivity was increased in STSAR90 cells when intracellular glutathione levels were reduced by buthionine sulfoximine. These results indicate that multidrug resistance due to P-glycoprotein-mediated drug efflux is not the only mechanism of doxorubicin resistance that occurs in sarcomas and that glutathione peroxidase-dependent detoxification of doxorubicin-induced oxygen radicals may contribute to clinical doxorubicin resistance.
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PMID:Increased glutathione peroxidase activity in a human sarcoma cell line with inherent doxorubicin resistance. 184 55

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

The emergence of drug resistance is a major obstacle to effective cancer chemotherapy. The identification of novel agents that serve as selective, potent and nontoxic modulators of drug resistance is thus an important goal for improving the success of cancer treatment. Thaliblastine (TBL), a plant alkaloid and P-glycoprotein (P-gp) inhibitor, is presently shown to fully reverse 490-fold resistance to Adriamycin (AdR) in a multidrug-resistant (MDR) human breast cancer cell line (MCF/AdR) that overexpresses P-gp, whereas the same treatment had no effect on AdR cytotoxicity in the drug-sensitive parental MCF-7 cells. Mechanistic studies showed that this striking resistance reversal was achieved without alteration of cellular levels of glutathione and without inhibition of glutathione S-transferase, glutathione peroxidase or P450 reductase by TBL, each of which is significantly altered in MCF/AdR cells, and each of which has been proposed to contribute to AdR resistance in this MDR line. Rather, resistance reversal by TBL can be entirely explained by this drug's capacity to restore the intracellular accumulation of AdR in the resistant cells. These results establish that MDR associated with P-gp overexpression can be fully reversed by the potent P-gp inhibitor TBL. They further indicate that although changes in multiple drug-metabolizing enzymes may accompany the development of MDR, these multiple biochemical alterations need not correspond to multiple functional determinants for drug resistance.
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PMID:Complete reversal by thaliblastine of 490-fold adriamycin resistance in multidrug-resistant (MDR) human breast cancer cells. Evidence that multiple biochemical changes in MDR cells need not correspond to multiple functional determinants for drug resistance. 756 98

Tumor tissues of untreated and cytostatic-agent-treated patients with nephroblastomas were investigated for expression of resistance-related proteins (P-glycoprotein, glutathione S-transferase-pi, glutathione peroxidase and topoisomerase II) to ascertain whether resistance proteins are changed after treatment. Tumor tissue was analyzed by means of mRNA. Twenty-three children were treated with actinomycin D and vincristine for 4 to 8 weeks. Eight children received no preoperative chemotherapy. In untreated patients, no expression of P-glycoprotein was seen, whereas, in the patients who were treated with actinomycin D and vincristine, 12 out of 23 tumors showed increased P-glycoprotein expression (> mean value). Although we found no difference between treated and untreated tumors for glutathione S-transferase-pi, we found significant differences in the expression of glutathione peroxidase. In the 8 untreated patients, 7 tumors showed low glutathione peroxidase (< mean value) and one high (> mean value) glutathione-peroxidase-mRNA content. With treatment, 11 tumors expressed low levels and 12 tumors high levels of mRNA. A significant positive correlation between P-glycoprotein and glutathione peroxidase was found. In addition, of the 8 untreated patients, 2 had low topoisomerase-II expression, and 6 high expression. With treatment, the expression was reduced in 18 tumors, and only 5 tumors had high levels of this protein. These results were confirmed by PCR and immunohistochemistry.
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PMID:Expression of resistance-related proteins in nephroblastoma after chemotherapy. 759 Dec 3

The levels of several potential indicators of resistance to cytostatic drugs were measured in leukaemic cells of a total of 64 adult patients with acute or chronic leukaemias before and during treatment and at relapse or recurrence of disease and compared with those of mononuclear cells from the bone marrow of healthy donors. The resistance factors included glutathione (GSH) and its associated enzymes glutathione-S-transferase (GST) and glutathione peroxidase (GPx) as well as O6-alkyguanine-DNA-alkyltransferase (ATase) and P-glycoprotein. Median values for most parameters were significantly higher in leukaemic cells than in those of normal donors although wide interindividual variation in the values of the various parameters, particularly GST, were seen. P-glycoprotein was measurable in 12.5% of untreated leukaemias but in none of the normal donors. The values of the parameters in untreated leukaemic patients were not statistically different from those at relapse or during disease progression. However, the median values for GSH, GST and GPx but not ATase in samples from untreated patients were significantly higher than those in samples taken during drug treatment. Patient response, disease-free survival or duration of remission did not correlate with the values of any of the parameters studied.
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PMID:Cytostatic drug resistance: parallel assessment of glutathione-based detoxifying enzymes, O6-alkylguanine-DNA-alkyltransferase and P-glycoprotein in adult patients with leukaemia. 790 32


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