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)

We have established preclinical models for the development of drug resistance to vincristine (a major drug used in the treatment of pediatric rhabdomyosarcoma) using cell lines. The RD cell line has a mutant P53 phenotype and does not have detectable P-glycoprotein (P-gp) or multidrug resistance-related protein (MRP) despite expressing low levels of mdr-1 mRNA, which encodes P-gp and mrp1 mRNA. Resistant variants of RD were derived by exposure to increasing concentrations of vincristine. This was repeated on six occasions, resulting in three cell lines which could tolerate 64 x the IC(50) concentration. Six independent agents were tested for their ability to prevent the development of resistance in this model. Despite at least 10 attempts, resistance did not develop in the presence of the multidrug resistance (MDR) modulators PSC833, VX710, and XR9576. This strongly suggests that these agents may delay or even prevent the development of resistance to vincristine. This was also confirmed in a second rhabdomyosarcoma cell line, Rh30. In contrast, the agents indomethacin (MRP1 modulator), CGP41251 (protein kinase C inhibitor), and dexrazoxane (putative MDR prevention agent) did not affect the development of resistance in the RD model. Characterization of the resistant cell lines indicated the presence of increased mdr-1 and P-gp expression, which resulted in resistance to the agents doxorubicin, etoposide, and vincristine but not cisplatin. The resistance could be modulated using PSC833 or VX710, confirming that functional P-gp is present. No apparent differences were seen between the resistant cell lines derived in the absence and presence of the various agents. These experiments strongly suggest that the development of MDR may be preventable using modulators of MDR and merit clinical studies to test this hypothesis.
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PMID:In vitro prevention of the emergence of multidrug resistance in a pediatric rhabdomyosarcoma cell line. 1159 14

Acquirement of drug resistance by tumor cells is a major chemotherapeutic problem. It is well known that typical multidrug resistance is caused by P-glycoprotein and multidrug resistance related protein (MRP1) which belong to the ATP binding cassette (ABC) transporter family. Ishikawa proposed that the ATP-dependent glutathione-S-conjugate export pump (GS-X pump) and phase III detoxification system are essential to drug metabolism, and this constituted a new concept in drug metabolism and the detoxification of xenobiotics. The GS-X pump has been revealed to belong to the ABC transporter family and suggested to the contribution to anticancer drug resistance. The GS-X pump actively effluxes the glutathione S-platinum (GS-Pt) complex. We cloned novel ABC transporter cDNA from the PC-14/CDDP cell line, and the cloned cDNA was designated as a short-type MRP homologue, SMRP. Further investigation suggested that SMRP is a splicing variant of MRP5. The MRP5 mRNA levels in tumors from lung cancer patients treated with platinum regimen were significantly higher than in tumors from patients treated with non-platinum regimens, and the MRP5 expression levels were correlate with the GCS expression levels that is the rate-limiting step enzyme in glutathione biosynthesis. These results suggested that MRP5 take part in the function of GS-X pump. Recently many transporter molecules belong to the ABC transporter family such as MRP family have been identified, and appear to express in various human tissues. It can be presumed that their molecules are affected by the disposition and metabolism of drugs, but their substrates are still unclear. If the substrate specificity is revealed in the future, it is expected that the anticancer agents transporter, moreover anti cancer drug resistance mechanisms, can be clarified. This review is cited in the cisplatin resistance and the GS-X pump, and finally describes an overview of the MRPs substrates recently clarified, mainly about anticancer drugs.
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PMID:The MRP family and anticancer drug metabolism. 1176 88

The ability of technetium-99m tetrofosmin (Tc-TF) scan to predict chemotherapy response in malignant lymphomas (ML) was compared with the predictive ability of P-glycoprotein (Pgp) and multidrug resistance related protein (MRP) expression. Before chemotherapy, 25 ML patients were enrolled in this study. Scans were performed 10 min after intravenous injection of Tc-TF. Immunohistochemical analyses were performed on ML specimen sections to evaluate Pgp and MRP expression. Chemotherapy response was evaluated in the first 1-2 years after completion of chemotherapy. Based on Tc-TF scan results, the mean tumor-to-background (T/B) ratio of the 15 patients with good response (3.23 +/- 0.56) was significantly higher than that of the 10 patients with poor response (1.18 +/- 0.11). All 15 patients with good response had positive Tc-TF scan results but negative Pgp and MRP expression. All 10 patients with poor response had negative Tc-TF scan results but positive Pgp or MRP expression. No significant differences in the incidences of good and poor response results were found for patients with Hodgkin's disease versus non-Hodgkin's lymphoma, with stage I-II versus stage III-IV, with age > 40 versus age < or = 40 years, or with B symptoms versus without B symptoms. Tc-TF scan results, which may represent either Pgp or MRP expression, accurately predict chemotherapy response in patients with ML.
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PMID:Using technetium-99m-tetrofosmin scan to predict chemotherapy response of malignant lymphomas, compared with P-glycoprotein and multidrug resistance related protein expression. 1183 97

The aim of this study was to investigate the relationships among technetium-99m tetrofosmin (Tc-TF) accumulation in parathyroid adenoma and the expression of P-glycoprotein (Pgp) or multidrug resistance related protein (MRP). Before operation, 33 patients with parathyroid adenomas (larger than 1.5 gm) were studied with parathyroid scintigraphy 10 minutes and 2 hours after intravenous injection of Tc-TF before operation. Immunohistochemical analyses (IHA) were performed on multiple nonconsecutive sections of operative parathyroid specimens to detect Pgp or MRP expression. According to the results of IHA, the 33 parathyroid adenomas were separated into four groups: (1) 2 adenomas with both positive Pgp and positive MRP expression, (2) 1 adenomas with positive Pgp but negative MRP expression, (3) 2 adenomas with negative Pgp but positive MRP expression, and (4) 28 adenomas with both negative Pgp and negative MRP expression. All of 28 adenomas in the group 4 could be detected by Tc-TF parathyroid imaging. All of 5 adenomas in the groups 1 to 3 could not be detected by TcTF parathyroid imaging (p < 0.05). Not only the size of parathyroid adenomas, but also significant Pgp or MRP expression limited the sensitivity of Tc-TF parathyroid imaging to localize parathyroid adenomas before operation.
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PMID:Detecting parathyroid adenoma using technetium-99m tetrofosmin: comparison with P-glycoprotein and multidrug resistance related protein expression--a preliminary report. 1192 4

Drug resistance is a major cause of the failure of anticancer chemotherapy. Multidrug resistance is often caused by overexpression of the P-glycoprotein (Pgp) or the multidrug resistance-related protein (MRP). In the present study, we compared daunorubicin (DNR) accumulation, subcellular distribution, and the effect of modulators on drug accumulation and subcellular distribution in the Pgp-expressing K562 cell line and the MRP-expressing HL60 cell line using reverse-transcriptase polymerase chain reaction, MTT (3-[4, 5-dimethylthiazol-z-yl]-2,5-diphenyltetrazolium bromide) drug cytotoxicity assay, fluorocytometry, and confocal laser scanning microscopy. The 2 resistant cell lines exhibit similar levels of resistance to DNR and decreased drug accumulation. Altered drug subcellular distribution in the resistant cell lines compared to that in the sensitive cell lines was shown and, moreover, differences in drug distributions between the 2 resistant cell lines were found. DNR fluorescence in the resistant HL60 cell line was distributed into punctate regions in the cytoplasm; the nucleus and other cytoplasm were almost negative. In contrast, the resistant K562 cells showed a bright fluorescent signal located in the peripheral cytoplasm and perinuclear region; the nucleus and other cytoplasmic regions showed no signal. Use of the modulator verapamil increased drug accumulation and restored the altered subcellular distribution of the drug in the 2 resistant cell lines. The Golgi apparatus inhibitor brefeldin A had similar action in the resistant HL60 line but had little effect in the resistant K562 line. Therefore, our study suggested that there were differences between the 2 resistant cell lines in the compartments sequestering DNR.
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PMID:Comparison of Pgp- and MRP-mediated multidrug resistance in leukemia cell lines. 1193 61

Several fluorescent probes have been used in functional studies to analyze drug transport in multidrug-resistant cells by fluorescent microscopy. Because many of these molecules have some drawbacks, such as toxicity, nonspecific background, or accumulation in mitochondria, new fluorescent compounds have been proposed as more useful tools. Among these substances, Bodipy-FL-Verapamil, a fluorescent conjugate of the drug efflux blocker verapamil, has been used to study P-glycoprotein activity in different cell types. In this study we tested by fluorescent microscopy the accumulation of Bodipy-FL-Verapamil in cell lines that overexpress either P-glycoprotein (P-gp) or multidrug resistance-related protein 1 (MRP1). Expression of P-gp and MRP1 was evaluated at the mRNA level by RT-PCR technique and at the protein level by flow cytometric analysis using C219 and MRP-m6 monoclonal antibodies. Results indicate that Bodipy-FL-Verapamil is actually a substrate for both proteins. As a consequence, any conclusion about P-gp activity obtained by the use of Bodipy-FL-Verapamil as fluorescent tracer should be interpreted with caution.
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PMID:The fluorescent probe Bodipy-FL-verapamil is a substrate for both P-glycoprotein and multidrug resistance-related protein (MRP)-1. 1196 84

There is considerable interest among basic and clinical researchers in novel drugs with activity against leukemia. The vast history of experience of traditional Chinese medicine (TCM) with medicinal plants may facilitate the identification of novel antileukemic compounds. In the present investigation, we tested 22 drugs for their activity toward CCRF-CEM cell lines: artesunate, artemisinin, baicalein, baicalin, berberine, bufalin, cantharidin, cephalotaxine, curcumin, daidzein, daidzin, diallyl disulfide, ginsenoside Rh2, glycyrrhizic acid, isonardosinon, homoharringtonine, nardosinon, nardofuran, puerarin, quercetin, tannic acid, and tetrahydronardosinon. As compounds from folk medicinal remedies are sometimes looked upon as alternative medicine with some hesitation or criticism, we investigated only chemically pure compounds and tested the drugs independently in two different laboratories in Germany and Australia. We used CCRF-CEM parental cells and doxorubicin-selected P-glycoprotein (P-gp)/MDR1-expressing CEM/ADR5000, vinblastine-selected P-gp/MDR1-expressing CEM/VLB(100), and epirubicin-selected multidrug resistance-related protein 1 (MRP1)-expressing CEM/E1000 sublines thereof. While CEM/ADR5000, CEM/VLB(100), and CEM/E1000 cells were highly resistant to the corresponding selecting agents, no or only minimal degrees of cross-resistance were observed to TCM drugs in both growth inhibition assay and MTT assay (range from 0.4- to 8-fold). Homoharringtonine, artesunate, and bufalin were most active among this panel of compounds. As shown by flow cytometry, artesunate significantly increased daunorubicin accumulation in CEM/E1000 cells, but not in CEM/VLB(100) or CCRF-CEM parental cells. Bufalin caused a small, but significant increase in daunorubicin accumulation in CEM/VLB(100) and CEM/E1000 cells. As artesunate and bufalin showed both antileukemic activity if applied alone and modulation activity in combination with daunorubicin in multidrug-resistant (MDR) cells, these two drugs may be suitable for novel combination treatment regimens to improve leukemia cell killing.
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PMID:Activity of drugs from traditional Chinese medicine toward sensitive and MDR1- or MRP1-overexpressing multidrug-resistant human CCRF-CEM leukemia cells. 1206 12

Gland size has been reported to have a major influence on localisation of parathyroid adenomas by technetium-99m methoxyisobutylisonitrile ((99m)Tc-MIBI) imaging. It has also been suggested that P-glycoprotein (Pgp) expression in parathyroid adenomas may influence localisation because false negative studies have been reported with large tumours and true positives with very small tumours. Therefore, the purpose of this study was to retrospectively evaluate the relationship between (99m)Tc-MIBI parathyroid imaging results and Pgp or multidrug resistance-related protein (MRP) expression in parathyroid adenomas. Before surgery, 47 patients with large parathyroid adenomas (larger than 1.5 g) underwent early and delayed parathyroid imaging, 10 min and 2 h after intravenous injection of (99m)Tc-MIBI. Immunohistochemical analyses (IHA) were performed, using multiple non-consecutive sections of the operative specimens, to detect Pgp or MRP expression. According to the results of IHA, the 34 parathyroid adenomas were separated into four groups: (1) three adenomas positive for both Pgp and MRP expression, (2) one adenoma positive for Pgp but negative for MRP expression, (3) four adenomas negative for Pgp but positive for MRP expression and (4) 39 adenomas with negative for both Pgp and MRP expression. All 39 adenomas in group 4 could be detected by (99m)Tc-MIBI parathyroid imaging. None of the eight adenomas in groups 1-3 could be detected by (99m)Tc-MIBI parathyroid imaging ( P<0.05). It is concluded that not only the size of parathyroid adenomas but also significant Pgp or MRP expression limits the sensitivity of (99m)Tc-MIBI imaging in localising parathyroid adenomas preoperatively.
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PMID:Technetium-99m methoxyisobutylisonitrile imaging for parathyroid adenoma: relationship to P-glycoprotein or multidrug resistance-related protein expression. 1254 33

The resistance of small cell lung cancer (SCLC) to anticancer drugs is a serious clinical problem often encountered during chemotherapy. Therefore, how to prevent this drug resistance need to be investigated. Multidrug resistance 1 (MDR1) gene and multidrug resistance-related protein (MRP) gene, two genes known to be associated with the development of drug resistance, are very common in SCLC. The purpose of this study was to evaluate retrospectively the relationship between chemotherapy responses to MDR1 gene encodes 170 kDa P-glycoprotein (Pgp) expression or MRP gene encodes 190 kDa MRP expression in SCLC. Before chemotherapy, multiple nonconsecutive sections of the bronchoscopy biopsy specimens of SCLC from 50 patients were analyzed immunohistochemically to detect Pgp and MRP expressions. Chemotherapy responses of the 50 patients were evaluated in the third month after completion of treatment by clinical and radiological methods. Of the 23 SCLC patients with poor response to chemotherapy, 11 had positive Pgp and MRP expressions, 2 had positive Pgp but negative MRP expressions, 6 had positive MRP but negative Pgp expressions, and 4 patients had negative Pgp and MRP expressions. All 27 SCLC patients with good response had negative Pgp and MRP expression. Immunohistochemical analyses of Pgp or MRP expression are potential tools for predicting patients' chemotherapy response in SCLC.
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PMID:Relationship between chemotherapy response of small cell lung cancer and P-glycoprotein or multidrug resistance-related protein expression. 1217 31

Non-invasive imaging methods in the evaluation of chemotherapy response in malignant tumours are currently being explored. Standard Nuclear Medicine procedures seem to offer the clinician a promising tool in the management of those oncologic patients, who might benefit from chemotherapy. Early studies focused on the relationship between radionuclides used in tumour diagnosis and factors associated with multidrug resistance (MDR). The tumour expression of P-glycoprotein (Pgp) and multidrug resistance-related protein-1 expression (MRP) have been suggested as important factors in the failure of chemotherapy. Most studies found an association between Pgp levels and (99m)Tc-sestamibi ((99m)Tc-MIBI) or (99m)Tc-Tetrofosmin uptake ((99m)Tc-TF). Currently investigations in nuclear medicine oncology are focusing on the potential role of radionuclide imaging in the assessment of chemotherapy. Recent papers discuss the usefulness of radionuclides as (99m)Tc-MIBI and (99m)Tc-TF as non-invasive procedures to predict and to monitor therapy response in patients affected by malignant tumours treatable using chemotherapy. This chapter will review the latest development in (99m)Tc-TF, giving an overview of recent investigations carried out using this radiotracer in therapy oncology, with emphasis on its potential role as predictor of tumour response.
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PMID:Tetrofosmin as predictors of tumour response. 1271 56


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