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)

Multidrug resistance (MDR) is one of the mechanisms of resistance to multiple cytotoxic drugs and is mediated by the expression of a membrane pump called the P-glycoprotein. Nifedipine is one of the calcium channel blocking agents which reverses MDR in vitro. Fifteen patients with various malignancies received nifedipine at three dose levels: 40 mg, 60 mg and 80 mg orally twice daily for 6 days. Etoposide was administered intravenously on day 2 in a dose of 150-250 mg m-2 and orally 150-300 mg twice daily on days 3 and 4. Cardiovascular effects of nifedipine were dose limiting and the maximum tolerated dose was 60 mg bid. Mean area under the plasma concentration curve (AUC0-00) and plasma half-life (beta) of nifedipine and its major metabolite MI at the highest dose level were 7.87 microM.h, 7.97 h and 4.97 microM.h, 14.0 h respectively. Nifedipine did not interfere with the pharmacokinetics of etoposide.
...
PMID:A phase I study on the reversal of multidrug resistance (MDR) in vivo: nifedipine plus etoposide. 173 28

In a previous study we suggested that, in addition to the reduced Adriamycin accumulation, part of the resistance in an Adriamycin-resistant human small cell lung carcinoma cell line (GLC4/ADR) could be explained by supposing a changed Adriamycin-DNA-topoisomerase II (Topo II) interaction. The present study showed that the Mr 170,000 P-glycoprotein was not overexpressed in GLC4/ADR and that verapamil did not reverse the Adriamycin resistance. GLC4/ADR expressed cross-resistance to teniposide, etoposide, 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), and mitoxantrone. Further investigations of the drug-Topo II interaction revealed that the decatenation activity of Topo II was two- to threefold reduced in both cellular and nuclear extracts from GLC4/ADR. Topo I activities appeared similar in extracts from GLC4/ADR and the parental sensitive cell line (GLC4). The slight increase in doubling time from 15 to 18 h, while the cell cycle distribution remained unchanged, could not account for the reduced Topo II activity in GLC4/ADR. Etoposide and m-AMSA-induced DNA cleavage was 5-fold reduced in cellular extracts from GLC4/ADR. Inhibition of the decatenation activity of Topo II in the presence of VP-16 and m-AMSA was increased twofold in the cellular extracts from GLC4/ADR. Therefore, these results suggest that resistance of GLC4/ADR to Adriamycin was in part due to the reduced drug-induced formation of the cleavage complex.
...
PMID:Reduced DNA topoisomerase II activity and drug-induced DNA cleavage activity in an adriamycin-resistant human small cell lung carcinoma cell line. 196 22

The aim of this work is to evaluate the relationship between P-glycoprotein expression in circulating blasts and clinical response in patients suffering from acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, and chronic myeloid leukemia in either lymphoid or myeloid blastic crisis. The results obtained show that: a) patients whose blasts express P-glycoprotein are resistant towards protocols including Doxorubicin, Daunorubicin, Etoposide, Mithramycin, Vincristine; b) P-glycoprotein can be expressed constitutively in some cases; c) P-glycoprotein does not appear to be the only mechanism responsible for resistance towards anthracyclines and Etoposide.
...
PMID:P-glycoprotein and drug resistance in acute leukemias and in the blastic crisis of chronic myeloid leukemia. 198 99

Etoposide (VP-16) is one of the most important anticancer agents available and is used in many chemotherapeutic regimens. To characterize resistance to this drug, we established a VP-16-resistant human ovarian cancer cell line, SKOV3/VP, by continuous stepwise exposure of SKOV3 cells to VP-16. The degree of resistance to VP-16 of SKOV3/VP was about 25 times that of the parent cell line (SKOV3), and SKOV3/VP showed cross-resistance to teniposide, adriamycin, CPT-11, and vincristine. The accumulation of [3H]-VP-16 observed in SKOV3/VP cells was about half that seen in SKOV3 cells, and the accumulation of Adriamycin by this resistant cell line was also lower than that of its parent. Overexpression of neither the multidrug resistance gene mdr-1, the multidrug-resistance-associated protein (mrp) gene, nor P-glycoprotein was detected using reverse transcriptase-polymerase chain reaction analysis and flow cytometry with MRK-16, a monoclonal antibody against P-glycoprotein. The topoisomerase II activity of nuclear extracts from SKOV3/VP cells was lower than that from the parental cells, as was the amount of DNA topoisomerase II, demonstrated by immunoblotting. These results suggest that the mechanism responsible for the multidrug resistance of this cell line may be attributable to changes on its DNA topoisomerase II and to its reduced accumulation of the drugs as compared with the parental line SKOV3.
...
PMID:Characterization of an etoposide-resistant human ovarian cancer cell line. 791 42

Over the past decade, DNA topoisomerase I and II appeared to be the targets of some antitumor agents: CPT-11 and Topotecan derived from Camptothecin which interact with topoisomerase I; Actinomycin D, Adriamycin and Daunorubicin, Elliptinium Acetate, Mitoxantrone, Etoposide and Teniposide, Amsacrine which interact with topoisomerase II. The multiple functions of these enzymes are important as they play a role during replication, transcription, recombination, repair and chromatine organisation. Particularly, they relax torsional constraints which appear when intertwined DNA strands are separated while replication fork or RNA polymerases are moving. To some extent, topoisomerase I and II are structurally and functionally different. Moreover, topoisomerase I is not indispensable for a living cell whereas topoisomerase II is. Drug-topoisomerase interaction which probably leads to antitumoral effect of the compounds studied in this review is not a trivial inhibition of the enzyme but rather a poisoning due to stabilization of cleavable complexes between the enzyme and DNA. These stabilized complexes are likely to induce apoptosis-like programmed cell death, which is characterised by DNA fragmentation. However, it appears that it is the collision of the replication fork with the drug-stabilized cleavable complex that is responsible for the cytotoxicity of the drug: poisoning of topoisomerases by antitumor agents leads to a new concept of "dynamic toxicity". Although they interact with a common target, topoisomerase II poisons have differential effects on macromolecules syntheses, cell cycle and chromosome fragmentation; a few compounds may produce free radicals. Because of these differential effects in addition to quantitative and qualitative variations of stabilized cleavable complexes, in particular DNA sequences on which topoisomerase II is stabilized, these antitumor agents do not resemble each other. Cellular resistance to topoisomerases poisons results of two principal types of alteration: target and/or drug transport modification. Decreased ability to form the cleavable complex in resistant cells may be the consequence of both decreased amount of topoisomerase or altered enzyme. On the other hand, overexpression of membrane P-glycoprotein, which pumps drugs out of the cell by an energy dependent process provokes a decreased accumulation of these drugs. Cross resistances to other drugs are mainly under control of these two different mechanisms of resistance. A complete knowledge of their individual effects and mechanisms of resistance would allow a better clinical use of topoisomerases poisons, especially when administered in combination chemotherapy.
...
PMID:[Poisons of DNA topoisomerases I and II]. 808 Oct 34

Multidrug resistance-associated protein (MRP) causes multidrug resistance (MDR) involving the anthracyclines and epipodophyllotoxins. Many studies show modulation of anthracycline levels and cytotoxicity in MRP-overexpressing cells, but there is limited data on the modulation of etoposide levels and cytotoxicity in MRP-overexpressing or in P-glycoprotein-expressing cells. Etoposide accumulation was 50% reduced in both the CEM/E1000 MRP-overexpressing subline and the CEM/VLB100 P-glycoprotein-expressing subline compared to the parental CEM cells, correlating with similar resistance to etoposide (200-fold) of the two sublines. For the CEM/VLB100 subline, the P-glycoprotein inhibitor SDZ PSC 833, but not verapamil, was able to increase etoposide accumulation and cytotoxicity. For the CEM/E1000 subline, neither SDZ PSC 833 nor verapamil had any effect on etoposide accumulation. However, verapamil caused a 4-fold sensitization to etoposide in this subline, along with an 80% decrease in cellular glutathione (P < 0.05). Buthionine sulfoximine (BSO), which depletes glutathione, also caused a 2.5-fold sensitization to etoposide with no effect on accumulation in the CEM/E1000 subline. In contrast, SDZ PSC 833 was able to increase daunorubicin accumulation in the CEM/E1000 subline (P < 0.05), but had no effect on daunorubicin cytotoxicity, or cellular glutathione. These results show that modulation of etoposide cytotoxicity in MRP-overexpressing cells may be through changes in glutathione metabolism rather than changes in accumulation and confirm that changes in drug accumulation are not related to drug resistance in MRP-overexpressing cells.
...
PMID:The relationship between modulation of MDR and glutathione in MRP-overexpressing human leukemia cells. 971 84

In this study, P-glycoprotein modulator effects on pharmacokinetics and central nervous system distribution of the chemotherapeutic agent etoposide were evaluated. The multidrug resistance transporter P-glycoprotein is expressed in normal tissues, and its physiological function is thought to be an excretory and/or protective one. To examine this further, we evaluated etoposide under steady-state and bolus dose conditions. In microdialysis infusion studies, etoposide 15 mg/kg/hr was administered to 12 rats. Rats received sodium cyanide (1 or 100 mM), trifluoperazine (30 mM) or cyclosporine (4.14 mM) via microdialysis probe at 3.5 hr after etoposide infusion initiation. High-dose sodium cyanide (100 mM) increased the etoposide BBR,corr from 0.09 +/- 0.03 to 0.85 +/- 0.35. Similarly, trifluoperazine significantly increased the BBR,corr (0.05 +/- 0.02 vs. 1.30 +/- 0.43), whereas cyclosporine had no effect. In bolus studies, etoposide (10-12 mg/kg) was given alone or concomitant to cyclosporine (5 mg/kg) or tamoxifen (13.5 mg/kg). Control etoposide total systemic clearance (ml/min/kg) was 29.3 +/- 13.0 vs. 16.0 +/- 1.9 and 22.6 +/- 5.3 for cyclosporine and tamoxifen treatments, respectively. Etoposide nonrenal clearance (ml/min/kg) values for cyclosporine (12.0 +/- 1.6) and tamoxifen (18.1 +/- 3.6) treatments was also decreased from controls (23.5 +/- 10.5). Etoposide renal clearance (ml/min/kg) values (5.7 +/- 2.5) were not significantly different from cyclosporine (4.0 +/- 0.7) or tamoxifen (4.6 +/- 1.7) treatments, respectively. In this study, the ability of sodium cyanide and trifluoperazine to alter etoposide BBR,corr, demonstrated that etoposide distribution into brain is partly controlled by an active transport process. Similarly, the results indicate cyclosporine inhibits etoposide transport at the canalicular membrane and/or etoposide P-450 metabolism.
...
PMID:Effects of P-glycoprotein modulators on etoposide elimination and central nervous system distribution. 986 72

Etoposide, an anti-neoplastic agent and a substrate of P-glycoprotein (P-gp), exhibits variable oral bioavailability. P-gp, the multidrug resistance gene (mdr1) product, has been considered as an absorption barrier against intestinal drug absorption. Terfenadine, an antihistamine, has been shown to be a P-gp inhibitor. The current study was designed to assess the effect of hydroxyzine, an antihistamine, on the transport of etoposide in the small intestine. Everted rat gut sacs were used to determine the absorption and exsorption of etoposide under different conditions, as rhodamine 123 was chosen to evaluate the role of P-gp in the drug interaction. The results showed that the transport of etoposide was significantly increased from the luminal site to the serosal site in the jejunum by 2- and 4-fold after 90 min in the presence of hydroxyzine and quinidine, respectively. A similar trend was observed in the ileal sacs. This in vitro exsorption study also demonstrated that hydroxyzine could reduce the efflux of etoposide to the luminal site in either jejunum or ileum. The effect of hydroxyzine on the pharmacokinetics of etoposide differed by the in vivo route of administration, thus assuming clinical importance for chemotherapeutic treatment.
...
PMID:Effect of hydroxyzine on the transport of etoposide in rat small intestine. 1129 Aug 74

Multidrug resistance conferred to cancer cells is often mediated by the expression of efflux transporter "pumps". It is also believed that many of the same transporters are involved in drug efflux from numerous normal endothelial and epithelial cell types in the intestine, brain, kidney, and liver. Etoposide transport kinetics were characterized in Caco-2 cells and in well established Madin-Darby canine kidney (MDCKII) cell lines that were stably-transfected with a human cDNA encoding P-glycoprotein (Pgp), human multidrug resistance protein (MRP1), or the canalicular multispecific organic anion (cMOAT) transporters to determine the roles of these transporters in etoposide efflux. Etoposide transport kinetics were concentration-dependent in the MDCKII-MDR1 and MDCKII-cMOAT cells. The apparent secretory Michaelis constant (Km) and carrier-mediated permeability (Pc) values for Pgp and cMOAT were 254.96 +/- 94.39 microM and 5.96 +/- 0.41 x 10(-6) cm/s and 616.54 +/- 163.15 microM and 1.87 +/- 0.10 x 10(-5) cm/s, respectively. The secretory permeability of etoposide decreased significantly in the basal to apical (B to A) (i.e., efflux) direction, whereas the permeability increased 2.3-fold in the apical to basal (A to B) direction in MDCKII-MDR1 cells in the presence of elacridar (GF120918). Moderate inhibition of etoposide efflux by leukotriene C4 (LTC4) was observed in MDCKII-cMOAT cells. Furthermore, etoposide inhibited LTC4 efflux, confirming the involvement of cMOAT. The flux of etoposide in MDCKII-MRP1 cells was similar to that in MDCKII/wt control cells. The current results demonstrate that the secretory transport mechanism of etoposide involves multiple transporters, including Pgp and cMOAT but not MRP1. These results demonstrate that Pgp and cMOAT are involved in the intestinal secretory transport of etoposide. Since the intestinal secretion of etoposide was previously reported in the literature, it also suggests that they may be involved in the in vivo intestinal secretion of etoposide; however, mechanistic in vivo studies are required to confirm this.
...
PMID:Delineating the contribution of secretory transporters in the efflux of etoposide using Madin-Darby canine kidney (MDCK) cells overexpressing P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), and canalicular multispecific organic anion transporter (cMOAT). 1190 Nov 1

Etoposide (VP16) is a potent inducer of DNA double-strand breaks (DSBs) and is efficiently used in small cell lung cancer (SCLC) therapy. However, acquired VP16 resistance remains an important barrier to effective treatment. To understand the underlying mechanisms for VP16 resistance in SCLC, we investigated DSB repair and cellular VP16 sensitivity of SCLC cells. VP16 sensitivity and RAD51, DNA-PK(cs), topoisomerase IIalpha and P-glycoprotein protein levels were determined in 17 SCLC cell lines. In order to unravel the role of RAD51 in VP16 resistance, we cloned the human RAD51 gene, transfected SCLC cells with RAD51 sense or antisense constructs and measured the VP16 resistance. Finally, we measured VP16-induced DSBs in the 17 SCLC cell lines. Two cell lines exhibited a multidrug-resistant phenotype. In the other SCLC cell lines, the cellular VP16 resistance was positively correlated with the RAD51 protein level. In addition, downregulation or overexpression of the RAD51 gene altered the VP16 sensitivity. Furthermore, the levels of the RAD51 and DNA-PK(cs) proteins were related to VP16-induced DSBs. The results suggest that repair of VP16-induced DSBs is mediated through both RAD51-dependent homologous recombination and DNA-PK(cs)-dependent nonhomologous end-joining and may be a determinant of the variation in clinical treatment effect observed in human SCLC tumors of identical histologic subtype. Finally, we propose RAD51 as a potential target to improve VP16 efficacy and predict tumor resistance in the treatment of SCLC patients.
...
PMID:The role of RAD51 in etoposide (VP16) resistance in small cell lung cancer. 1271 36


1 2 3 Next >>

---