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)

The purpose of this study was to clarify the clinical efficacy of multidrug chemotherapy for aggressive adult T-cell leukemia (ATL). We report the therapeutic results of treatment of patients with aggressive ATL undertaken between 1986 and 1995. A total of 120 newly diagnosed patients with a performance status of 0-3 and aged < 70 years at diagnosis were entered into the study. Clinical features, including clinical subtypes, serum levels of lactate dehydrogenase and blood urea nitrogen, the response to chemotherapy, and doses of individual chemotherapeutic agents, were evaluated. Of the 120 patients enrolled, 97 had acute-type and 23 lymphoma-type ATL. The complete response rate and median survival of these patients were 25.3% and 9 months, respectively. The 2- and 5-year survival rates were 18.4% and 8%, respectively, and five patients have been alive for > 5 years and are disease-free. These long-term survivors had good prognostic factors at diagnosis. There was no correlation between the doses of the various chemotherapeutic agents and the survival duration. These results indicate that ordinary combined chemotherapy has limited ability to improve the prognosis of aggressive ATL. Our previous study indicated that expression of P-glycoprotein in ATL cells might be involved in resistance to chemotherapeutic agents, particularly doxorubicin, vincristine, and etoposide. Therefore, new therapeutic strategies will be necessary to improve the prognosis of ATL patients.
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PMID:Treatment for adult T-cell leukemia. 927 34

Currently 40% of the world's population is still at risk of becoming infected with malaria, which is an even more worrisome disease because of drug resistance and multidrug resistance. Research on drug resistance is suggesting new ways to attack the parasite by designing selectively toxic compounds. At Washington University, a study has been centering on how malarial parasites developed resistance to antimalarial drugs. A new class of compounds have been developed that block haem polymerization to haemazoin and kill the parasite. These hexadentate metal complexes that bypass the current resistance mechanisms are made from aspirin and are being tested in animals. A new resistance gene also been identified that transports chloroquine out of the parasite or blocks the drug's influx, leaving the parasite unharmed. In addition, a gene associated with mefloquine resistance was isolated at Harvard University. A large number drug transporter inhibitors have also been identified, but none is sufficiently selective for the parasite's transporter. In Oxford, UK, recently, the low-resolution structure of the human multidrug resistant P-glycoprotein was also solved, which might permit the design of modified antimalarial drugs. Exploiting the differences between parasite and human enzymes may also provide new drug targets. The crystal structure of a complex between plasmepsin, a parasite aspartate protease that initiates the digestion of hemoglobin, and an inhibitor has also been revealed. The crystal structure of lactate dehydrogenase (LDH) from Plasmodium falciparum has also been determined finding a big difference around the active site of the malarial enzyme and mammalian LDH. Parasite enzymes are being researched by other scientists elsewhere. At the University of Montpellier, France, the work on the parasite's choline carrier is more advanced. One of three compounds that kill parasites will be chosen for clinical studies.
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PMID:Beating the malaria parasite at its own game. 928 Aug 13

The 110-kD lung resistance protein (LRP) is overexpressed in P-glycoprotein-negative multidrug-resistant cell lines and most likely involved in the multidrug resistance (MDR) of these cell lines. To determine the clinical significance of LRP, we have studied LRP expression of leukemic blasts and its association with clinical outcome in patients with de novo acute myeloid leukemia (AML). LRP expression of leukemic blasts obtained from peripheral blood or bone marrow of previously untreated patients (n = 86) was determined by immunocytochemistry by means of monoclonal antibody LRP-56. LRP expression at diagnosis was detected in 31 (36%) patients. LRP expression was independent of age and sex of the patients, French-American-British subtype, cytogenetic abnormalities, and lactate dehydrogenase levels, but correlated with white blood cell count (P = .01). Eighty-two patients received standard induction chemotherapy that included cytarabine and MDR drugs (daunorubicin in most patients, additional etoposide in the majority of patients). The complete remission rate of induction chemotherapy was 72% (95% confidence interval [CI] = 61% to 82%) for the total study population. The complete remission rate was 81% (95% CI = 67% to 91%) for patients without LRP expression but only 55% (95% CI = 36% to 74%) for patients with LRP expression (P = .01). Overall survival and disease-free survival were estimated according to Kaplan-Meier in 82 and 59 patients, respectively. Overall survival was significantly longer in patients without LRP expression than in patients with LRP expression. At a median follow-up of 16 months, median overall survival was 17 months (95% CI = 12 to 38 months) for LRP-negative patients but only 8 months (95% CI = 4 to 12 months) for -positive patients (P = .006). Disease-free survival was 9 months (95% CI = 7 to 11 months) for LRP-negative patients and 6 months (95% CI = 5 to 8 months) for -positive patients (P = .078). Outcome was best in patients lacking both LRP and P-glycoprotein expression. In conclusion, LRP predicts for poor outcome and thus the LRP gene appears to be another clinically relevant drug resistance gene in AML.
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PMID:Expression of the lung resistance protein predicts poor outcome in de novo acute myeloid leukemia. 947 13

Cremophor EL (CR) is a solubilizing agent and a modulator of P-glycoprotein (P-gp)-mediated anticancer multidrug resistance. The present study was undertaken to evaluate whether doxorubicin (Dox) pharmacokinetics, therapeutic activity and cardiotoxicity in Swiss albino mice is modified when combined with CR treatment. CR (2.5 ml/kg, i.p) given simultaneously with Dox (20 mg/kg, i.p.) increased Dox levels in plasma, heart, liver and kidneys of healthy mice. Using an Ehrlich ascites carcinoma (EAC)-bearing mice experimental model, CR (2.5 ml/kg) improved the survival and antitumor activity of Dox. The enhanced antitumor activity of Dox was related to a significant increase in EAC tumor cellular Dox content by CR. Furthermore, CR (1 microg/ml) potentiated the in vitro cytotoxicity of Dox in cultured EAC cells. In healthy mice, Dox-induced mortality was markedly reduced by simultaneous treatment with CR. CR enhanced DOX-induced increase in plasma lactate dehydrogenase, creatine phosphokinase (CPK) and CPK-MB isozyme activities, as well as the cardiac malondialdehyde level. CR also increased Dox-induced focal necrotic myocardial lesions. These findings suggest that CR increased DOX antitumor activity and cardiotoxicity as a result of enhancing its bioavailability, and decreased Dox-induced mortality in mice by a mechanism not yet defined.
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PMID:Effect of Cremophor EL on the pharmacokinetics, antitumor activity and toxicity of doxorubicin in mice. 984 Jul 28

Infection and inflammation impose a suppression in the expression and activity of several drug transporters and drug-metabolizing enzymes in liver. In the intestine, cytochrome P450 3A (CYP3A), P-glycoprotein (PGP/mdr1), and the multidrug resistance-associated protein 2 (MRP2) are important barriers to the absorption of many clinically important drugs; thus, the expression and activity of these proteins were examined in inflammation. Transport and metabolism were determined in jejunum segments isolated at 24 h from endotoxin-treated or control rats (n = 8) mounted in Ussing chambers. Transport and metabolism of (3)H-digoxin, 5-carboxyfluorescein (5-CF), amiodarone (AM), and 7-benzyloxyquinoline (7-BQ) were measured for 90 min in the presence and absence of inhibitors. Reverse transcription-polymerase chain reaction was used to measure mRNA levels. As compared with controls, levels of mdr1a and mrp2 mRNA were significantly decreased by approximately 50% in the jejunum of LPS-treated rats. Corresponding reductions in the basolateral-->apical efflux of digoxin, AM, and 5-CF were observed, resulting in significant increases in the apical-->basolateral absorption of these compounds. Intestinal CYP3A mRNA levels and CYP3A-mediated metabolism of 7-BQ and AM were also decreased by approximately 50 to 70% (p < 0.05) in the LPS group. Mannitol permeability and lactate dehydrogenase release were not altered. These studies indicate that endotoxin-induced inflammation imposes a reduction in the intestinal expression and activity of PGP, mrp2, and CYP3A in rats, which elicits corresponding changes in the intestinal transport and metabolism of their substrates. Hence, infection and inflammatory diseases may impose variability in drug bioavailability through alterations in the intestinal expression and activity of drug transporters and metabolic enzymes.
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PMID:Suppression of drug-metabolizing enzymes and efflux transporters in the intestine of endotoxin-treated rats. 1470 16

To evaluate the intestinal permeability of poorly water-soluble compounds, it is of importance to completely dissolve them in a medium and to avoid precipitation during experiments. This study was undertaken to find an agent possessing a high-solubilizing capacity and exhibiting minimal modulating impact on membrane integrity and absorption systems such as passive diffusion and carrier-mediated permeation. Phenytoin dissolution was compared in the presence of seven solubilizing agents at concentrations of 1, 2, or 5% using a centrifugation method. The capacity to dissolve phenytoin was great in beta-cyclodextrin (beta-CD) and hydroxypropyl beta-cyclodextrin, followed by Tween 80. Those of methanol, dimethyl sulfoxide, dimethyl acetoamide, and polyethylene glycol 400 were much lower than expected. One percent beta-CD did not alter the absorption of fluorescein isothiocyanate-dextran 4,000 or the release of protein and lactate dehydrogenase into in situ loop contents, suggesting that 1% beta-CD had no significant impact on the integrity of the intestinal membrane. One percent beta-CD also did not alter the absorption of caffeine, ceftibuten, or rhodamine 123 from in situ jejunal loops, indicating no interference with passive diffusion and active transports mediated by a peptide transporter and P-glycoprotein. In conclusion, 1% beta-CD is a suitable solubilizing agent for evaluating in situ intestinal absorption of poorly water-soluble compounds.
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PMID:Beta-cyclodextrin as a suitable solubilizing agent for in situ absorption study of poorly water-soluble drugs. 1526 50

The present investigation attempts to increase intestinal permeability and hence absorption of biopharmaceutic classification system (BCS) Class III (cefotaxime sodium (CX)) and Class IV (cyclosporin A (CSA)) drugs by employing certain absorption enhancers. Drugs were co-perfused with sodium caprate (SC, 0.25% w/v), piperine (P, 0.004% w/v) and sodium deoxycholate (SD, 1.0% w/v) separately in rat in situ single pass intestinal perfusion model. These additives increased intestinal permeability (P(app)) and absorption rate constant (K(a)) up to two and fourfold, respectively. SC exhibited substantial absorption enhancement of both CX and CSA, while SD and P enhanced absorption of CX and CSA, respectively. Co-administration of SC significantly enhanced peroral bioavailability of CX (from 29.4 +/- 1.7 to 69.6 +/- 3.2) and CSA (from 18.4 +/- 15.6 to 49.6 +/- 25.1) in rats, while P increased bioavailability of CSA (from 18.4 +/- 15.6 to 33.1 +/- 17.7). Transmission electron microscopy of intestinal mucosa revealed that SC and SD act on lipid and protein domains of absorptive membrane. P showed no effect on intestinal P(app) and oral bioavailability of CX but has a profound effect on CSA, a known P-glycoprotein (P-gp) substrate. These results indicated that P enhances intestinal absorption of CSA by modulating P-gp mediated efflux transport. Release of lactate dehydrogenase in situ from intestinal mucosa in the presence of absorption enhancer was taken as index of its local toxicity. All the absorption enhancers showed significantly less release of LDH compared to positive control, sodium dodecyl sulfate (60% w/v). Overall, the data indicate that the features of these commonly used food ingredients or endogenous bile salts can effectively improve bioavailability of various BCS Class III and Class IV drugs.
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PMID:In situ and in vivo efficacy of peroral absorption enhancers in rats and correlation to in vitro mechanistic studies. 1624 20

The aim of this study is to evaluate the potential use of first-generation (G1) polyamidoamine (PAMAM) dendrimers as drug carriers to enhance the permeability, hence oral absorption, of drugs that are substrates for P-glycoprotein (P-gp) efflux transporters. G1 PAMAM dendrimer-based prodrugs of the water-insoluble P-gp substrate terfenadine (Ter) were synthesized using succinic acid (suc) or succinyl-diethylene glycol (suc-deg) as a linker/spacer (to yield G1-suc-Ter and G1-suc-deg-Ter, respectively). In addition, the permeability of G1-suc-deg-Ter was enhanced by attaching two lauroyl chains (L) to the dendrimer surface (L2-G1-suc-deg-Ter). All of the G1 dendrimer-terfenadine prodrugs were more hydrophilic than the parent drug, as evaluated by drug partitioning between 1-octanol and phosphate buffer at pH 7.4 (log K(app)). The influence of the dendrimer prodrugs on the integrity and viability of human Caucasian colon adenocarcinoma cells (Caco-2) was determined by measuring the transepithelial electrical resistance (TEER) and leakage of lactate dehydrogenase (LDH) enzyme, respectively. The LDH assay indicated that the dendrimer prodrugs had no impact on the viability of Caco-2 cells up to a concentration of 1 mM. However, the IC(50) of the prodrugs was lower than that of G1 PAMAM dendrimer because of the high toxicity of terfenadine. Measurements of the transport of dendrimer prodrugs across monolayers of Caco-2 cells showed an increase of the apparent permeability coefficient (P(app)) of terfenadine in both apical-to-basolateral (A --> B) and basolateral-to-apical (B --> A) directions after its conjugation to G1 PAMAM dendrimer. The A --> B P(app) of the dendrimer prodrugs was significantly greater than B --> A P(app). The surface-modified dendrimer prodrug L2-G1-suc-deg-Ter showed the highest A --> B permeability among the conjugates.
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PMID:Synthesis and assessment of first-generation polyamidoamine dendrimer prodrugs to enhance the cellular permeability of P-gp substrates. 1735 18

Recent studies suggest that capsaicin (Cap), a major constituent of hot pepper, may affect the function and permeability of the intestinal mucosa in vitro. However, the relationships between the dose of Cap and the barrier and/or transporter functions on intestinal epithelial cells are unknown. The aim of this study was to investigate whether Cap initiates cellular injury and alter epithelial permeability in Caco-2 cells. Cellular toxicity, as measured using a lactate dehydrogenase release assay, was not observed at high concentrations of Cap (up to 300 microM). When cell viability was measured by a WST-1 assay (tetrazolium salt-based assay), damage to Caco-2 monolayers was observed at doses of 200 and 300 microM of Cap. The barrier function of tight junctions was assessed by measuring transepithelial electrical resistance (TEER) in Caco-2 cells. Treatment of Caco-2 cells with Cap at doses above 100 microM significantly decreased the TEER compared to treatment with buffer alone for 2 h (p<0.05). We next examined the effects of Cap on the activity of P-glycoprotein (P-gp) found on transcellular transporters. At doses of 100 and 200 microM, Cap inhibited the transport of rhodamine 123 by P-gp-mediated efflux in Caco-2 cells. Cap thus exhibited inhibitory effects on P-gp. The results of this study indicate that Cap, a dietary phytochemical, causes functional and structural changes in Caco-2 cell monolayers at noncytotoxic doses (less than 100 microM of Cap). The concomitant administration of Cap with drugs that are substrates of P-gp might increase the plasma concentrations of such drugs.
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PMID:Effects of capsaicin on cellular damage and monolayer permeability in human intestinal Caco-2 cells. 1791 78

Treatment of children with acute lymphoblastic leukemia (ALL) is based on P-glycoprotein (P-gp)-dependent cytostatics. We assessed the P-gp function in blast cells as a possible prognostic factor and its influence on the overall survival. P-gp function was measured using the verapamil-sensitive Rhodamine efflux. Cell samples from 7 of 45 (16%) patients revealed rhodamine-efflux positive blasts. There were no relations between the presence of P-gp, clinical characteristics (age, sex, hepatomegaly, and splenomegaly) and initial laboratory parameters (immunophenotype, white blood cells count, and serum lactate dehydrogenase) in ALL. P-gp activity plays a negative role, both for a remission achieved on day 33 and for susceptibility to steroid therapy. Children bearing rhodamine-efflux positive blasts had a significantly shorter 5-year overall survival of 35%, as compared with 74% in those negative for P-gp function. Lack of any association with clinical characteristic and initial laboratory parameters suggests that presence of P-gp is an independent prognostic factor.
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PMID:P-glycoprotein activity predicts outcome in childhood acute lymphoblastic leukemia. 1956 43


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