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

---

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

Tc-99m 2 methoxy-isobutyl-isonitrile (99mTc-MIBI), also called Sestamibi, is a safe and effective scanning agent in solid tumours. Its use in imaging lesions in multiple myeloma has been studied in 21 patients with either multiple myeloma (19/21) or monoclonal gammopathy of undetermined significance (MGUS) (2/ 21). 99mTc-MIBI scanning was positive in 14 patients, 13 with active myeloma and one patient with MGUS showing possible transformation to a more accelerated phase. In seven patients 99mTc-MIBI scanning was negative. In four of them, the result was unexpected, as they had the features of active myeloma. All four were either primarily or secondarily resistant to chemotherapy, with high total cumulative doses of doxorubicin. Overexpression of P-glycoprotein associated with multidrug resistance could be a factor, as it has been shown that 99mTc-MIBI is actively eliminated from the cell by P-glycoprotein. With this assumption, sensitivity of the scanning technique in this series is 100%, and the specificity 88%. No toxicity was experienced by any patient. 99mTc-MIBI scanning is a useful adjunct to the investigation of multiple myeloma, and may have potential as an in vivo test for multidrug resistance.
...
PMID:The use of 99mTc-MIBI scanning in multiple myeloma. 895 99

A new human myeloma cell line, 8226/MDR10V, was selected from a P-glycoprotein-positive cell line, 8226/Dox40, in the continuous presence of doxorubicin and verapamil. MDR10V cells are 13-fold more resistant to doxorubicin and 4-fold more resistant to vincristine than the parent cell line, Dox40. Chemosensitizers are also less effective in reversing resistance in the MDR10V compared to the Dox40 cells. Despite higher resistance to cytotoxic agents, MDR10V expresses 40% less P-glycoprotein in the plasma membrane compared to Dox40; however, total cellular P-glycoprotein is the same in both cell lines. Confocal immunofluorescence microscopy shows 2.5-fold more P-glycoprotein in the cytoplasm of MDR10V cells as compared to Dox40 cells. The cytoplasmic location of P-glycoprotein in the MDR10V cells is associated with a redistribution of doxorubicin. In Dox40 cells, doxorubicin is concentrated in the nucleus, whereas in MDR10V cells, 90% of doxorubicin is found in the cytoplasm. In the presence of equivalent intracellular doxorubicin, there was a decrease in DNA-protein crosslinks in the MDR10V cell line compared to the Dox40 cell line. This finding is in agreement with the intracellular doxorubicin fluorescence studies showing less doxorubicin in the nuclei of MDR10V cells compared to Dox40 cells. Verapamil is less effective in increasing doxorubicin accumulation in the nuclei of MDR10V cells compared to Dox40 cells. Processing of P-glycoprotein from the endoplasmic reticulum to the medial Golgi was identical between the two cell lines as determined by endoglycosidase H sensitivity of newly sensitized P-glycoprotein. No mutations were found in MDR1 cDNA from MDR10V cells compared to Dox40 cells. These results suggest that resistance to chemosensitizing agents plus cytotoxic drugs is associated with a redistribution of P-glycoprotein from the plasma membrane to the cytoplasm, which in turn reduces the amount of cytotoxic drug reaching the nucleus.
...
PMID:Evidence for cytoplasmic P-glycoprotein location associated with increased multidrug resistance and resistance to chemosensitizers. 896 98

VX-710 or (S)-N[2-Oxo-2-(3,4,5-trimethoxyphenyl)acetyl]-piperidine-2-carboxylic acid 1,7-bis(3-pyridyl)-4-heptyl ester, a novel non-macrocyclic ligand of the FK506-binding protein FKBP12, was evaluated for its ability to reverse P-glycoprotein-mediated multidrug resistance in vitro. VX-710 at 0.5-5 microM restored sensitivity of a variety of multidrug resistant cells to the cytotoxic action of doxorubicin, vincristine, etoposide or paclitaxel, including drug-selected human myeloma and epithelial carcinoma cells, and human MDR1 cDNA-transfected mouse leukemia and fibroblast cells. Uptake experiments showed that VX-710 at 0.5-2.5 microM fully restored intracellular accumulation of [14C]doxorubicin in multidrug resistant cells, suggesting that VX-710 inhibits the drug efflux activity of P-glycoprotein. VX-710 effectively inhibited photoaffinity labeling of P-glycoprotein by [3H]azidopine or [125I]iodoaryl azidoprazosin with EC50 values of 0.75 and 0.55 microM. Moreover, P-glycoprotein was specifically labeled by a tritiated photoaffinity analog of VX-710 and unlabeled VX-710 inhibited analog binding with an EC50 of 0.75 microM. VX-710 also stimulated the vanadate-inhibitable P-glycoprotein ATPase activity 2- to 3-fold in a concentration-dependent manner with an apparent k(a) of 0.1 microM. These data indicate that a direct, high-affinity interaction of VX-710 with P-glycoprotein prevents efflux of cytotoxic drugs by the MDR1 gene product in multidrug resistant tumor cells.
...
PMID:Cellular and biochemical characterization of VX-710 as a chemosensitizer: reversal of P-glycoprotein-mediated multidrug resistance in vitro. 907 9

The purpose of this study was to evaluate to what extent the ability of various chemosensitisers (CS) to reverse P-glycoprotein-associated multidrug resistance (MDR) is reduced when tested in physiological serum protein concentrations. Utilising drug sensitivity and accumulation assays, the CS were tested in medium containing 10% fetal bovine serum and in 100% horse or human serum. Two RPMI 8226 human myeloma sublines were used which express different levels of P-glycoprotein. The CS were tested at various concentrations, including clinically achievable blood levels. When using the CS at high doses, wide differences were observed in the extent CS activity was diminished by serum. Verapamil, cyclosporin A and quinine were not affected, quinidine and medroxyprogesterone acetate were moderately inhibited, and amiodarone and trifluoperazine were largely inactivated. When the CS were used at concentrations achievable in humans, the activity of all agents except quinine was markedly reduced by serum. With respect to the extent to which CS activity was diminished by serum, good statistical correlation (r > 0.90, P < 0.001) was found between the use of cytotoxicity and drug accumulation assays, horse and human serum or cell lines with high and low levels of P-glycoprotein, respectively. These studies demonstrated that physiological serum protein concentrations can profoundly diminish the MDR reversing activity of particular CS. Some drugs, such as amiodarone and trifluoperazine, are largely inactivated by serum when used at a wide range of concentrations. Other agents, such as verapamil and cyclosporin A, are essentially unaffected when used at high doses but markedly inhibited at concentrations achievable in humans. These data suggest that in vitro studies of CS in medium containing low serum protein concentrations can result in misleading conclusions regarding the potential clinical activity of such agents.
...
PMID:Serum can inhibit reversal of multidrug resistance by chemosensitisers. 908 67

The purpose of the present study was to evaluate whether intermittent exposure to a constant dose of doxorubicin selects for multidrug resistance (MDR) in RPMI 8226 human myeloma cells and, if so, to determine the molecular mechanism. In an attempt to approximate clinical doxorubicin treatment in vitro, cells were exposed to a fixed dose of doxorubicin for 4 d alternating with growth in drug-free medium for 17 d. An MDR subline emerged, termed 8226/DOXint5, which was 3-4-fold resistant to doxorubicin, etoposide and m-AMSA, and 1.6-fold resistant to vincristine. Sensitivity to docetaxel, melphalan and cisplatin was normal. Verapamil normalized vincristine sensitivity but had little effect on resistance to the other agents. Cellular uptake and retention of daunorubicin and vincristine were reduced by approximately 10%. The 8226/DOXint5 cells showed diminished DNA topoisomerase IIalpha expression and increased expression of the multidrug resistance protein MRP. Expression of MDR1/P-glycoprotein was not detected. Immunostaining showed 70% of the cells to over-express the lung-resistance protein LRP. This new MDR myeloma cell line may prove to be a useful model for the development of strategies to overcome low-level, multifactorial MDR, which might be a common phenomenon in clinical myeloma treated with doxorubicin.
...
PMID:Intermittent exposure to doxorubicin in vitro selects for multifactorial non-P-glycoprotein-associated multidrug resistance in RPMI 8226 human myeloma cells. 913 43

Multiple myeloma is a disease which is generally considered responsive to chemotherapy; however, essentially all patients who respond to drug treatment will relapse and die of drug-resistant disease. This disease is therefore considered a paradigm for studying the development of acquired drug resistance in the clinic. Natural product agents are frequently used in the treatment of myeloma, especially vincristine and doxorubicin. Studies using human myeloma cell lines have shown that the MDR1 gene product, P-glycoprotein (Pgp), is responsible for conferring drug resistance to natural products and glucocorticoids. We have developed assays to measure the expression of MDR1/Pgp in human myeloma specimens. These assays include immunocytochemistry, flow cytometry, and RT/PCR. Human myeloma cell lines, 8226/Dox, that are resistant to natural product agents and overexpress MDR1/Pgp are important for standardizing results and offer a means of comparing inter- and intra-patient results. Assays which measure both the presence and function of Pgp are necessary to determine the role of Pgp in clinical drug resistance in patients with myeloma.
...
PMID:Detection of multidrug resistance gene expression in multiple myeloma. 920 7

Approximately 15-30% of acute myeloid leukaemia (AML) patients are primarily resistant to chemotherapy, and 60-80% of patients who achieve complete remission will inevitably relapse and succumb to their disease. The multidrug resistant (MDR) phenotype has been suspected as a major mechanism of therapy failure in AML; it is one of the best understood mechanisms of resistance to anticancer drugs. The classical MDR phenotype is characterized by the reduced ability of cells to accumulate drugs as compared to normal cells. The increased drug efflux is due to the activity of a 170 kDa glycoprotein, the P-glycoprotein (Pgp), a unidirectional drug-efflux pump which is encoded by the MDR1 gene. While studies of myeloid leukaemia and myeloma have provided the best evidence for the potential association between Pgp expression and clinical outcome, the lack of standardized methods for MDR detection and perhaps even more importantly, inconsistencies in the interpretation of MDR expression data account for divergent results in the literature. The clinicians' strong interest in MDR stems from the availability of agents capable of interfering with MDR, at least in vitro. If these laboratory results were reproducible in vivo, reversal of MDR would offer a rare opportunity to incorporate laboratory experience into the clinical management of patients.
...
PMID:Classical multidrug resistance in acute myeloid leukaemia. 923 13

Intrinsic and acquired multidrug resistance (MDR) in many human cancers may be due to expression of the multidrug transporter P-glycoprotein (Pgp), which is encoded by the mdr1 gene. There is substantial evidence that Pgp is expressed both as an acquired mechanism (e.g., in leukemias, lymphomas, myeloma, and breast and ovarian carcinomas) and constitutively (e.g., in colorectal and renal cancers) and that its expression is of prognostic significance in many types of cancer. Clinical trials of MDR modulation are complicated by the presence of multiple-drug-resistance mechanisms in human cancers, the pharmacokinetic interactions that result from the inhibition of Pgp in normal tissues, and, until recently, the lack of potent and specific inhibitors of Pgp. A large number of clinical trials of reversal of MDR have been undertaken with drugs that are relatively weak inhibitors and produce limiting toxicities at doses below those necessary to inhibit Pgp significantly. The advent of newer drugs such as the cyclosporin PSC 833 (PSC) provides clinicians with more potent and specific inhibitors for MDR modulation trials. Understanding how modulators of Pgp such as PSC 833 affect the toxicity and pharmacokinetics of cytotoxic agents is fundamental for the design of therapeutic trials of MDR modulation. Our studies of combinations of high-dose cyclosporin (CsA) or PSC 833 with etoposide, doxorubicin, or paclitaxel have produced data regarding the role of Pgp in the clinical pharmacology of these agents. Major pharmacokinetic interactions result from the coadministration of CsA or PSC 833 with MDR-related anticancer agents (e.g., doxorubicin, daunorubicin, etoposide, paclitaxel, and vinblastine). These include increases in the plasma area under the curve and half-life and decreases in the clearance of these cytotoxic drugs, consistent with Pgp modulation at the biliary lumen and renal tubule, blocking excretion of drugs into the bile and urine. The biological and medical implications of our studies include the following. First, Pgp is a major organic cation transporter in tissues responsible for the excretion of xenobiotics (both drugs and toxins) by the biliary tract and proximal tubule of the kidney. Our clinical data are supported by recent studies in mdr-gene-knockout mice. Second, modulation of Pgp in tumors is likely to be accompanied by altered Pgp function in normal tissues, with pharmacokinetic interactions manifesting as inhibition of the disposition of MDR-related cytotoxins (which are transport substrates for Pgp). Third, these pharmacokinetic interactions of Pgp modulation are predictable if one defines the pharmacology of the modulating agent and the combination. The interactions lead to increased toxicities such as myelosuppression unless doses are modified to compensate for the altered disposition of MDR-related cytotoxins. Fourth, in serial studies where patients are their own controls and clinical resistance is established, remissions are observed when CsA or PSC 833 is added to therapy, even when doses of the cytotoxin are reduced by as much as 3-fold. This reversal of clinical drug resistance occurs particularly when the tumor cells express the mdr1 gene. Thus, tumor regression can be obtained without apparent increases in normal tissue toxicities. In parallel with these trials, we have recently demonstrated in the laboratory that PSC 833 decreases the mutation rate for resistance to doxorubicin and suppresses activation of mdr1 and the appearance of MDR mutants. These findings suggest that MDR modulation may delay the emergence of clinical drug resistance and support the concept of prevention of drug resistance in the earlier stages of disease and the utilization of time to progression as an important endpoint in clinical trials. Pivotal phase III trials to test these concepts with PSC 833 as an MDR modulator are under way or planned for patients with acute myeloid leukemias, multiple myeloma, and ovarian carcinoma.
...
PMID:Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein. 927 28

Although chemotherapy effectively reduces the plasma cell burden in multiple myeloma (MM), the disease recurs. MM includes circulating and bone marrow (BM) localized components. A large majority of circulating CD11b+ MM B cells (81%) express an IgH VDJ rearrangement identical to that of autologous BM plasma cells. Unlike plasma cells, these monoclonal circulating B cells exhibit dye and drug transport activity before and throughout chemotherapy. Drug resistance was measured as the ability to export the fluorescent dye Rhodamine123 (Rh123) or the drug adriamycin, using flow cytometry. The role of P-glycoprotein 170 (P-gp), the multidrug transporter, was defined by cyclosporin A (CsA)-sensitive dye export. Only 8% to 11% of BM-localized plasma cells exported dye with the majority retaining dye, identified as bright staining. Circulating leukemic plasma cells were also unable to export dye and remained Rh123(bright). However, 53% of circulating clonotypic MM B cells exhibited CsA-sensitive dye export. BM plasma cells taken before or after initiation of first line chemotherapy were equally unable to export dye. Thus in myeloma, differentiation to the plasma cell stage is accompanied by a loss of P-gp function, although P-gp phenotypic expression is retained. In contrast, for monoclonal gammopathy of undetermined significance (MGUS), 54% of BM-localized plasma cells exported dye, comparable to the 53% of circulating MGUS B cells that also exported dye, suggesting that the apparent defect in P-gp function is unique to myeloma plasma cells. Virtually all BM plasma cells in MM retained the drug adriamycin, consistent with their initial drug sensitivity in vivo, in contrast to circulating MM B cells, or to T cells in BM or blood. Thus, circulating B cells appear to be the predominant drug resistant component of the MM B-lineage hierarchy. This report suggests that successful therapeutic strategies will be those that target circulating B cells. Chemosensitization methods involving inhibition of P-gp are likely to improve depletion of these cells by compromising their ability to exclude drug. This work suggests that circulating clonotypic B cells should be monitored in clinical trials to confirm their depletion and the overall efficacy of novel treatment strategies.
...
PMID:Deficient drug transporter function of bone marrow-localized and leukemic plasma cells in multiple myeloma. 934 62

The development of multidrug resistance (MDR) is a major obstacle to improving treatment outcomes in multiple myeloma. Recent studies have indicated that several specific mechanisms of MDR may be involved in clinically refractory multiple myeloma patients, such as expression of P-glycoprotein (P-gp), expression of the lung-resistance protein (LRP) and suppression of apoptosis via expression of Bcl-2. The emergence of these mechanisms of MDR in multiple myeloma is enhanced by exposure to chemotherapeutic agents. Recently, clinical reversal of MDR by noncytotoxic P-gp modulators such as verapamil, cyclosporin A (CsA), and PSC 833 was explored in acute leukemia and multiple myeloma. Preliminary results from clinical phase I/II trials indicate that reversal of MDR via modulation of P-gp is possible and that coadministration of these MDR modulators with chemotherapeutic agents alters the plasma pharmacokinetics of chemotherapeutic agents. Phase II and III clinical trials investigating the efficacy of these and other agents in the reversal of MDR in hematologic malignancies are ongoing.
...
PMID:Drug resistance in multiple myeloma. 940 59


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---