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)

Eight anthracycline analogs that have been shown to modulate multidrug resistance (Friche et al., Biochem. Pharmacol., 39, 1721-1726; 1990) were tested for their inhibitory effect on the photolabelling of P-glycoprotein. We photoaffinity labelled P-glycoprotein in daunorubicin (DNR) resistant Ehrlich ascites tumour cells (EHR2/DNR +) with a [125I]iodinated Bolton-Hunter derivative of daunorubicin ([125I]iodomycin) and with [3H]azidopine. The photolabelling of P-glycoprotein by [125I]iodomycin was inhibited more than 50% by 10 microM (1000-fold molar excess) of DNR (52%), N,N-dibenzyl-DNR (52%), and N-benzyladriamycin-14-valerate (AD-198) (85%). Vincristine at 10 microM inhibited [125I]iodomycin labelling of P-glycoprotein by 95%. Thus vincristine was more potent than any of the eight anthracyclines tested, despite its relatively low lipophilicity. Increasing the concentration of DNR, AD-198 and N,N-dibenzyl-DNR to 40 microM resulted in 90, 99.5 and 99.5% inhibition of P-glycoprotein labelling by [125I]iodomycin, respectively. In comparison with the other anthracycline analogs, N,N-dibenzyl-DNR and Ad-198 were also found to exert the greatest inhibition of [3H]azidopine labelling of P-glycoprotein (about 90% at 100-fold molar excess). The solvents Cremophor EL and Tween 80 (30 micrograms ml-1; 0.003% v/v), which are modulators of multidrug resistance in EHR2/DNR + cells, also inhibited [125I]iodomycin labelling > 90%. We showed earlier that there is a correlation between the lipid solubility within the anthracycline group of MDR-associated drugs and their ability to enhance DNR accumulation in EHR2/DNR + cells but a corresponding correlation to lipophilicity when it comes to the inhibitory effect on the specific photolabelling of Pgp ligand binding sites could not be demonstrated. Neither could a correlation between the modulating effect of the analogs on DNR accumulation and inhibition on the labelling of Pgp be demonstrated. With increasing lipophilicity of the analogs it seems that the chemical structure plays a lesser role, and the degree of lipophilicity becomes a more important feature.
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PMID:Effect of anthracycline analogs on photolabelling of p-glycoprotein by [125I]iodomycin and [3H]azidopine: relation to lipophilicity and inhibition of daunorubicin transport in multidrug resistant cells. 809 88

1,3,5-Triazacycloheptanes were synthesized and examined for reversal of the multidrug resistance dependent on P-glycoprotein. Most of these compounds increased the intracellular uptake of vinblastine in multidrug-resistant mouse leukemia P388/ADR cells without influence upon the vinblastine accumulation in P388/S cells. The efficacy of 1,5-dibenzyl-1,3,5-triazacycloheptanes in increasing the vinblastine accumulation was in the order of 2,4-dithioxo (5) > 2-oxo-4-thioxo (4) approximately 4-(methylthio)-2-oxo (6) > 2,4-dioxo (2). The efficacy was further increased when the benzyl group was converted to a chlorobenzyl group. Among these compounds, 6c [1,5-bis(4-chlorobenzyl)-1,5,6,7-terahydro-4-(methylthio)-2H-1,3,5 - triazepin-2-one] potentiated the in vitro cell growth-inhibitory effect of vinblastine, adriamycin, and mitomycin C on P388/ADR cells and prolonged the life span of P388/ADR-bearing mice in combined therapy with vinblastine more than vinblastine alone.
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PMID:Novel inhibitors for multidrug resistance: 1,3,5-triazacycloheptanes. 854 83

P-glycoprotein (Pgp) is a major ABC transporter responsible for multidrug-resistance (MDR) in cancer chemotherapy. Pre-clinical MDR modulation studies identified promising chemosensitizers, but none are in the clinic yet. Two novel progesterone-derived carbamates (11-carbamic acid N,N-dibenzyl progesterone ester and 11-carbamic acid N,N-dibutyl progesterone ester) were examined as potential chemosensitizers in the Pgp-expressing human colon cancer line HCT-15, applying the classical MDR-drugs paclitaxel and doxorubicin. The major findings were: (1) Pgp was expressed in the HCT-15 cells in both the cell and the nuclear membranes, (2) at the low dose range of 1-5 microM, each new candidate: (i) increased cytotoxicity of doxorubicin (15-fold) and (separately) of paclitaxel (40-fold), (ii) induced an increase in intracellular accumulation, 60% (4h) for doxorubicin and 300% (18h) for paclitaxel, (iii) reduced drug efflux from the cell, 2-fold and 4-fold for doxorubicin and for paclitaxel, respectively. Based on detailed kinetic analysis, using liposomes to model paclitaxel diffusion through cell membranes, efflux slowdown can be attributed to reduction in the rate constant of drug diffusion through Pgp, and not to Pgp blockage. Chemosensitization was consistently-better for paclitaxel (cytosol-operating) than for doxorubicin (nuclear-operating) implying linkage between P-glycoprotein localization and loci of drug action. Mapping intracellular locations of MDR-pumps may assist therapeutic strategies.
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PMID:Novel steroid carbamates reverse multidrug-resistance in cancer therapy and show linkage among efficacy, loci of drug action and P-glycoprotein's cellular localization. 2055 61