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)

Rhodamine 123 is a fluorescent dye that localizes in mitochondria, is a substrate for the multidrug resistance pump, and is retained for long periods of time by carcinoma cells. 17 beta-Estradiol causes GH4C1 cells (rat pituitary tumor cells) to lose rhodamine 123 fluorescence faster than untreated cells. We found that estradiol induces accumulation of the mRNA for the multidrug resistance pump 3-5-fold, with maximum induction occurring within 1 day at 10(-9) M estradiol. Immunoblot analysis demonstrated that estradiol induces a protein of 150 kDa that reacts with an antibody to P-glycoprotein, the multidrug resistance pump. The reduced retention of rhodamine 123 caused by estradiol is prevented by verapamil and cyclosporin, inhibitors of the pump. A clone resistant to the effects of estradiol on rhodamine 123 has greatly reduced levels of mRNA for the pump. The effect of estradiol is more marked on rhodamine 123 retention than it is on that of rhodamine 110 or tetramethylrhodamine methyl ester. We conclude that estradiol enhances rhodamine 123 efflux by inducing the multidrug resistance gene. The specificity for rhodamine 123, compared with other analogs, may be caused by differences in accessibility to the pump.
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PMID:Estradiol induction of rhodamine 123 efflux and the multidrug resistance pump in rat pituitary tumor cells. 842 69

Lipophilic cationic compounds accumulate more rapidly in the mitochondria of many carcinoma-derived cells than in non-transformed cells, thus leading to their pronounced cytotoxic effects on carcinoma cells. In this report, in order to measure tumoricidal effects vs cytotoxicity to normal hematopoietic progenitors, we studied the sensitivity of committed human hematopoietic cells in vitro and two human carcinoma cell lines (2008 ovary carcinoma cells and HT29 colon cells) toward two such compounds, rhodamine-123 and phosphonium salt II-41. Continuous exposure of human marrow cells to rhodamine-123 or phosphonium salt II-41 for 7 and 14 days produced dose-related inhibition of colony formation of erythroid burst-forming units (BFU-E), erythroid colony forming units (CFU-E), and CFU-granulocyte/macrophage (CFU-GM). The average values of IC50 for several different human bone marrows are approximately 0.9-1.1 microM for rhodamine-123 toward BFU-E, CFU-E and CFU-GM, and 31-38 microM for phosphonium salt II-41 toward the same hematopoietic progenitors. These IC50 values are similar for each type of hematopoietic progenitors. In each case, rhodamine-123 appears to be at least 30-fold more growth suppressive than phosphonium salt II-41 in these in vitro colony assays. In addition, the sensitivity of these hematopoietic progenitors toward these two compounds is comparable to the inhibition of colony formation for the two human carcinoma cell lines. The lack of differences in the sensitivity among the various hematopoietic progenitors in vitro may disagree with previous studies showing there are vast differences in the state of cell cycle for these hematopoietic progenitor cells. However, these observations about the cytotoxicity in vitro can be explained by assuming that the cytotoxicity of these compounds depends on other factors such as differentiation processes, which result in the appearance of many or very active mitochondria. Alternatively, the lack of differences in the sensitivity of the in vitro colony formation can also be attributed to a reported decrease in expression of P-glycoprotein, a multidrug efflux pump, in the differentiating hematopoietic progeny cells.
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PMID:Sensitivity of committed hematopoietic progenitor cells in vitro (BFU-E, CFU-E, CFU-GM) and two human carcinoma cell lines toward rhodamine-123 and phosphonium salt II-41. 845 Jun 73

Previous controversy has risen from the purported equivalence of the volume-sensitive chloride channels with P-glycoprotein. The aim of this study was to investigate the association between expression of volume-sensitive Cl- channels and the process of malignant transformation of cervical epithelial cells. We studied the activations of volume-sensitive and cAMP-mediated chloride currents in various human cervical squamous cells that were representative of different stages of cervical carcinogenesis, i.e., normal cervical epithelium, low-grade cervical intraepithelial neoplasia, carcinoma in situ, and invasive carcinoma using the whole-cell patch clamp technique. The volume-sensitive chloride channels, however, were significantly activated only in the four cervical cancer cell lines, primary culture cells of carcinoma in situ, and invasive cancer of the cervix. The expression of volume-sensitive chloride currents was independent of the state of human papillomavirus positivity. When these cells were exposed to hypotonic shock, the cells swelled, and outward rectified chloride currents were observed. These effects were readily reversed by returning the cells to isotonic medium. In addition, 4,4'-diisothiocyanatostilbene-2,2-disulfonic acid, 1,9-dideoxyforskolin, and verapamil reversibly abolished the volume-sensitive Cl- currents. In contrast, none of the cells from normal cervices and human papillomavirus-immortalized cell lines, the in vitro equivalent of low-grade cervical intraepithelial neoplasia, developed substantial chloride currents on exposure to hypotonicity. cAMP-mediated chloride currents were ubiquitously activated in all cervical squamous cells, regardless of the stages of carcinogenesis. This is the first report suggesting an in vivo association between the development of volume-sensitive chloride currents and human carcinogenesis.
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PMID:Volume-sensitive chloride channels associated with human cervical carcinogenesis. 852 96

The multidrug-resistance (MDR)-reversing ability of the catamphiphilic drugs could be mediated through their interaction with the membrane phospholipids. This could lead directly (through changes in membrane permeability and fluidity) and/or indirectly (through inhibition of P-glycoprotein phosphorylation via inhibition of the phosphatidylserine-dependent protein kinase C or changes in the conformation and functioning of the membrane-integrated proteins via changes in the structure organization of the surrounding membrane bilayer) to the reversal of MDR. Using differential scanning calorimetry and NMR techniques and artificial membranes composed of phosphatidylcholine or phosphatidylserines we found a significant correlation between the MDR-reversing activity of the drugs in doxorubicin-resistant human breast carcinoma MCF-7/DOX and murine leukaemia P388/DOX tumour cells (data taken from the literature) and their ability to interact with phosphatidylserines. Trans- and cis-flupentixol were found to interact most strongly with both the phospholipids, followed by trifluoperazine, chlorpromazine, triflupromazine, flunarizine, imipramine, quinacrine and lidocaine. Differences in the interaction of trans- and cis-flupentixol with the phospholipids studied are suggested to be responsible for their different MDR-reversing ability. Verapamil showed moderate membrane activity, assuming that the membrane interactions are not the only reason for its high MDR-reversing ability. Amiodarone showed very strong interactions with phosphatidylserines and is recommended for further MDR-reversal studies.
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PMID:Membrane interactions of some catamphiphilic drugs and relation to their multidrug-resistance-reversing ability. 854 89

It has been suggested that expression of the P-glycoprotein transmembrane efflux pump (PGP), encoded by the multi-drug resistance (MDR1) gene, may play a role in the protection of epithelial tissues from a variety of local and systemic toxins. We report that in approximately 50% (6/11) of the population, MDR1 messenger RNA levels in the normal urinary epithelium are comparable to those found in the highest expressing tissues in the body, and suggest a role for PGP in the normal bladder urothelium. MDR1 mRNA levels in the normal urothelium do, however, vary over a 60-fold range between individuals, and furthermore are uniformly significantly lower (about 6-fold, P</=0.01) in all low-grade bladder carcinoma samples. On the basis of these observations we conclude that low MDR1 mRNA levels are a uniformly consistent characteristic of low-grade bladder tumours, and hypothesize that high MDR1 expression plays a role in protection of the normal bladder from carcinogen exposure, and that individuals with low normal bladder MDR1 mRNA levels may consequently be at an increased risk of developing bladder cancer. Furthermore,the low level of MDR1 expression generally found in low grade superficial tumours may predispose them to additional carcinogen exposure and in this way contribute to possible tumour progression. In addition, MDR1 mRNA levels were observed to be elevated in a significant proportion (approximately 25%, 8/30, P = 0.015) of high grade tumours compared to low grade samples, and may therefore represent a marker of bladder tumour progression.
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PMID:High level expression of the multidrug resistance (MDR1) gene in the normal bladder urothelium: a potential involvement in protection against carcinogens? 863 Nov 51

Dolastatins 10 and 15 are small peptides isolated from the marine sea hare Dolabella auricularia that have been shown to interact with tubulin. Their growth-inhibitory properties were compared using panels of human ovarian and colon-carcinoma cell lines. Both agents were very potent inhibitors of cell growth, with dolastatin 10 being an average of 9.1-fold more potent than dolastatin 15 [mean 50% inhibitory concentrations (IC50 values) 2.3 x 10(-10) and 2.1 x 10(-9) M, respectively; P < 0.05] and more potent than paclitaxel or vinblastine. While neither dolastatin exhibited marked cross-resistance in cisplatin- or etoposide-resistant cell lines, contrasting effects were observed using an acquired doxorubicin-resistant (CH1doxR, 100-fold resistant, P-glycoprotein overexpressing) cell line. Resistance was significantly higher to dolastatin 15 (12.7-fold) than to dolastatin 10 (only 3.2-fold; P < 0.05) and was reversible in both cases by verapamil. In vivo, using a s.c. advanced-stage human ovarian carcinoma xenograft and equitoxic doses, greater activity was observed with dolastatin 10 (6.1-day growth delay) versus 0.4 days for dolastatin 15. A radioimmunoassay for dolastatin 10 (limit of detection in mouse plasma 5 ng/ml) was developed. The rabbit antiserum aslo cross-reacted by 65% with dolastatin 15. Comparative mouse pharmacokinetics following i.v. administration of 1 mg/kg showed that both compounds are rapidly eliminated, but with a shorter second-phase half-life (t1/2 beta) being observed for dolastatin 15 (being detectable for only up to 4 h post-administration), the t1/2 beta being 3 times longer for dolastatin 10. In addition, areas under the plasma concentration-time curve (AUC values) were 1.6-fold higher for dolastatin 10 (333 versus 208 ng ml-1 h). Plasma binding of dolastatin 10 exceeded 90%. The highly sensitive RIA will be useful for pharmacokinetic studies in conjunction with the planned phase I clinical trials of these novel, extremely potent, tubulin-binding agents, of which dolastatin 10 appears to possess the more promising preclinical features.
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PMID:Antitumour evaluation of dolastatins 10 and 15 and their measurement in plasma by radioimmunoassay. 864 96

The multidrug resistance phenotype of human breast carcinoma MCF-7/AdrVp cells is characterized by overexpression of a 95-kilodalton membrane glycoprotein (p95), accompanied by a marked reduction in intracellular anthracycline accumulation, without overexpression of P-glycoprotein or the multidrug resistance protein. We discovered that the mRNA of the H19 gene is overexpressed in MCF-7/AdrVp cells relative to parental MCF-7 cells or drug-sensitive MCF-7/AdrVp revertant cells. H19 is an imprinted gene with an important role in fetal differentiation, as well as a postulated function as a tumor suppressor gene. Another p95-overexpressing multidrug-resistant cell line, human lung carcinoma NCI-H1688, also displays high levels of H19 mRNA. In contrast, several multidrug-resistant cell lines that overexpress P-glycoprotein or the multidrug resistance protein do not have higher levels of H19 mRNA than their drug-sensitive counterparts. This is the first report of H19 gene overexpression accompanying any form of drug resistance. The association of H19 and p95 gene expression in drug resistance warrants further study.
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PMID:H19 gene overexpression in atypical multidrug-resistant cells associated with expression of a 95-kilodalton membrane glycoprotein. 867 37

Multidrug resistance (MDR), especially that associated with overexpression of MDR1 and its product, P-glycoprotein (Pgp), is thought to play a role in the outcome of therapy for some human tumors; however, a consensus conclusion has been difficult to reach, owing to the variable results published by different laboratories. Many factors appear to influence the detection of Pgp in clinical specimens, including its low and heterogeneous expression; conflicting definitions of detection end points; differences in methods of sample preparation, fixation, and analysis; use of immunological reagents with variable Pgp specificity and avidity and with different recognition epitopes; use of secondary reagents and chromogens; and differences in clinical end points. Also, mechanisms other than Pgp overexpression may contribute to clinical MDR. The combined effect of these factors is clearly important, especially among tumors with low expression of Pgp. Thus, a workshop was organized in Memphis, Tennessee, to promote the standardization of approaches to MDR1 and Pgp detection in clinical specimens. The 15 North American and European institutions that agreed to participate conducted three preworkshop trials with well-characterized MDR myeloma and carcinoma cell lines that expressed increasing amounts of Pgp. The intent was to establish standard materials and methods for a fourth trial, assays of Pgp and MDR1 in clinical specimens. The general conclusions emerging from these efforts led to a number of recommendations for future studies: (a) although detection of Pgp and MDR1 is at present likely to be more reliable in leukemias and lymphomas than in solid tumors, accurate measurement of low levels of Pgp expression under most conditions remains an elusive goal; (b) tissue-specific controls, antibody controls, and standardized MDR cell lines are essential for calibrating any detection method and for subsequent analyses of clinical samples; (c) use of two or more vendor-standardized anti-Pgp antibody reagents that recognize different epitopes improves the reliability of immunological detection of Pgp; (d) sample fixation and antigen preservation must be carefully controlled; (e) multiparameter analysis is useful in clinical assays of MDR1/Pgp expression; (f) immunostaining data are best reported as staining intensity and the percentage of positive cells; and (g) arbitrary minimal cutoff points for analysis compromise the reliability of conclusions. The recommendations made by workshop participants should enhance the quality of research on the role of Pgp in clinical MDR development and provide a paradigm for investigations of other drug resistance-associated proteins.
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PMID:Methods to detect P-glycoprotein-associated multidrug resistance in patients' tumors: consensus recommendations. 1180 18

An in vitro study was designed to evaluate the uptake of sestamibi (MIBI) in P-glycoprotein (Pgp) and glutathione-associated (GSH) multidrug-resistant (MDR) cell lines. MIBI uptake was studied in various human breast carcinoma cell lines, i.e. in wild-type (MCF7/wt) cells, in adriamycin-resistant (MCF7/adr) cells which express Pgp and in melphalan-resistant (MCF7/mph) cells with increased levels of GSH. The effects of buthiomine sulphoximine (BSO) and verapamil on MIBI uptake were also studied in the MCF7/mph and MCF7/adr cells respectively. The cells were incubated for 1 h with a dose of 0.1 MBq thallium-201 and technetium-99m MIBI. Both MIBI and 201Tl uptakes were higher for MCF7/mph cells than for the other cells studied. The mean MIBI uptake in MCF7/adr cells was significantly lower than that in MCF7/wt cells (1.9%+/-0.5% vs 3. 1%.0.6%; P <0.01). Verapamil treatment increased the MIBI uptake in MCF7/adr cells (to 2.6%.0.3%; P <0.05). Treatment of MCF7/mph cells with BSO resulted in a significant reduction in GSH content (from 243.2+/-81.1 nmol/mg protein to 17.6+/-4.4 nmol/mg protein; P <0. 001). However, MIBI uptake in BSO-treated and untreated MCF7/mph cells was similar (4.43%+/-0.5% and 5.93%+/-1.7%, respectively; P >0. 1). This study suggests that the uptake of MIBI is not diminished by glutathione-associated drug resistance and that MIBI uptake in a tumour sample does not necessarily indicate that a cancer is sensitive to drugs.
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PMID:Technetium-99m sestamibi uptake in human breast carcinoma cell lines displaying glutathione-associated drug-resistance. 869 63

The present study demonstrated that poly(oxypropylene) and poly(oxyethylene) block copolymer pluronic L61 (L61)-hypersensitized multidrug-resistant CHRC5 Chinese hamster ovary cells and MCF-7/ADR human breast carcinoma cells to the cytotoxic action of doxorubicin (Dox). CHRC5 and MCF-7/ADR cells manifested 290- and 700-fold increases, respectively, in their sensitivity to Dox/L61 formulation compared with free Dox. Their sensitive counterparts Aux-B1 and MCF-7 displayed only marginal or no increase at all in their response to Dox/L61. The study of the drug transport performed by flow cytometry showed that L61 enhanced the drug uptake and reduced the P-glycoprotein-mediated drug efflux. Visualization of Dox subcellular distribution in CHRC5 cells by fluorescent microscopy revealed that Dox was sequestered in cytoplasmic vesicles, whereas incubation of the cells with Dox/L61 altered the drug compartmentalization by releasing the drug from these vesicles and shifting it to the nucleus. These findings suggested that the hypersensitive response of multidrug-resistant cells to the action of Dox/L61 was caused by an increase in the drug accumulation and changes in its subcellular distribution.
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PMID:Hypersensitizing effect of pluronic L61 on cytotoxic activity, transport, and subcellular distribution of doxorubicin in multiple drug-resistant cells. 870 95


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