Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the interaction between the multidrug transporter, P-glycoprotein, and two compounds that interact with it: vinblastine, a classical substrate of the pump, and verapamil, a classical reverser. Steady-state levels of accumulation of these two drugs were determined in a multidrug resistant P388 leukemia cell line, P388/ADR. The time course of accumulation of these drugs, and the effect of energy starvation and the presence of chloroquine on the level of their steady-state accumulation were quite disparate. Vinblastine inhibited the accumulation of verapamil whereas it enhanced the accumulation of daunomycin, another classic substrate of P-glycoprotein. Verapamil did not compete with the intracellular binding sites of vinblastine. In all these aspects, vinblastine behaved as a typical substrate of P-glycoprotein but verapamil did not. Our data suggest that verapamil is a reverser of P-glycoprotein but that its intracellular accumulation is not affected by this membrane-bound transporter.
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PMID:Drug accumulation in the presence of the multidrug resistance pump: dissociation between verapamil accumulation and the action of P-glycoprotein. 960 21

P-glycoprotein (Pgp) mediates drug accumulation defects in malignant cells in vitro. It confers resistance to multiple drugs including paclitaxel, an agent useful in treating malignancies including acute leukemia. Pgp-mediated drug resistance appears to be due to primary active drug-transport as well as other effects on membrane permeability, but the relative contribution of each is unclear. Flow cells are useful for differentiating transport-mediated efflux from altered membrane permeability, but their utility is limited to attached cells. We developed a novel flow cell to study drug efflux kinetics in suspension culture cells and examined paclitaxel efflux in resistant CEM/VLB100 leukemia cells, which overexpress Pgp, compared with its sensitive CEM parent line. Paclitaxel efflux from both cell lines was described by bi-exponential kinetics. The predominant initial rapid component increased linearly with paclitaxel concentration, consistent with passive efflux, and was faster in CEM/VLB100 than CEM cells. The slow terminal component of efflux was also more rapid for CEM/VLB100 than CEM, and was saturable (V(max)= 9.1 +/- 1.1 versus 3.5 +/- 0.3 pmol/min/10(7) cells, respectively) at a lower paclitaxel concentration than the parental CEM cells (k(m) = 63 +/- 46 nM versus 144 +/- 56 nM, respectively). In CEM/VLB100 cells, this saturable component was inhibited by verapamil and was temperature-sensitive, consistent with Pgp-mediated transport. Verapamil also inhibited the rapid component of efflux, suggesting additional effects on membrane permeability. Our studies show that the present technique is useful for studying drug transport and that effects of Pgp on membrane permeability contribute significantly to the net drug-accumulation defect.
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PMID:A flow cell assay for evaluation of whole cell drug efflux kinetics: analysis of paclitaxel efflux in CCRF-CEM leukemia cells overexpressing P-glycoprotein. 1115 98

Multidrug resistance mediated by the multidrug resistance-associated protein MRP1 is associated with decreased drug accumulation, which is in turn dependent on cellular glutathione. We have reported that verapamil, an inhibitor of drug transport, caused a decrease in cellular glutathione in CCRF-CEM/E1000 MRP1-overexpressing leukaemia cells (Biochem Pharmacol 55;1283--9, 1998). We now demonstrate that other inhibitors of MRP1-mediated drug transport (e.g. MK571, indomethacin, genistein, and nifedipine) deplete cellular glutathione in these leukaemia cells (>30% decrease; P < 0.01) while having no effect on the parental CCRF-CEM cells. However, treatment with etoposide or vincristine (at similar molar concentrations) caused a 20% decrease in glutathione. Verapamil-stimulated glutathione transport correlated with MRP1 expression in a series of drug-resistant cells, and glutathione was quantitatively recovered in the extracellular media. Further, verapamil-stimulated glutathione transport was rapid (50% decrease in 10 min), dose-dependent, and inhibited by vanadate, an inhibitor of ATPase activity, but not by sulphobromophthalein (BSP) or methionine, inhibitors of hepatic glutathione transporters. Incubation of CCRF-CEM/E1000 cells in 25 mM glutathione not only showed that verapamil-mediated efflux occurred against the concentration gradient, but also demonstrated the MRP1-mediated uptake of glutathione (P < 0.01 compared to the parental CCRF-CEM cells), which was not inhibited by vanadate. These results demonstrate that while MRP1 transports glutathione in the presence of inhibitors of drug transport, there is no convincing evidence for co-transport of glutathione with drug. They further demonstrate that MRP1 mediates the facilitated transport of glutathione into the MRP1-overexpressing CEM/E1000 cells, suggesting that MRP1 may play a major role in cellular glutathione homeostasis.
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PMID:Verapamil-stimulated glutathione transport by the multidrug resistance-associated protein (MRP1) in leukaemia cells. 1144 50

The MDR1 P-glycoprotein (P-gp) actively extrudes a wide variety of structurally diverse cytotoxic compounds out of the cell, is widely expressed in the epithelial cells of kidney, liver and intestine, and in the endothelial cells of brain and placenta, and plays an important role in drug resistance. We measured the accumulation of Rhodamine 123 (Rho123), a substrate of P-gp, into a drug sensitive and a drug resistant strain of the human leukemia cell line K562, as function of Rho123 concentration. With the aid of a mathematical transformation, we used the accumulation of Rho123 into the sensitive cells as a surrogate measure for the internal concentration of the probe in the resistant cells, and were thus able to measure the kinetic parameters of drug efflux pumping by P-gp. Drug pumping was half-saturated at an external Rho123 concentration of 7.2E-06+/-1.1E-06 M, and displayed a co-operative behaviour with a Hill number of 1.94+/-0.32. Verapamil could be shown to inhibit Rho123 efflux uncompetitively.
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PMID:A kinetic study of Rhodamine123 pumping by P-glycoprotein. 1685 69

Flavonoids are components of plant foods and of many herbal medicines taken in combination with anticancer drugs. We have examined the potential of flavonoids to affect the accumulation and cytotoxicity of 3 cytotoxic drugs [vinblastine (VLB), daunorubicin (DNR), and colchicine (COL)] that are substrates for the ABC transporter, P-glycoprotein in a vinblastine-resistant T-cell leukemia, CEM/VBL(100), that overexpresses P-glycoprotein. The effects of the flavonoids on accumulation and cytotoxicity of these drugs were different depending on the P-gp substrate used. Most of the 30 flavonoids tested decreased DNR accumulation in the VBL-resistant, but not sensitive, leukemia cells. By contrast, flavonoids that inhibited DNR accumulation enhanced the accumulation of fluorescently labeled vinblastine. None of these flavonoids affected COL accumulation. The effects of the flavonoids on the cytotoxicities of these drugs paralleled their effects on accumulation; the same flavonoids decreased DNR cytotoxicity but increased VLB cytotoxicity and had no effect on COL. Verapamil reversed the accumulation deficit and cytotoxicity of all three P-gp substrates. These effects correlated with the effects of flavonoids on P-gp-ATPase activity. Flavonoids that decreased DNR accumulation stimulated DNR-activated P-gp ATPase, whereas flavonoids that increased fluorescently labeled VLB accumulation inhibited VBL-stimulated P-gp ATPase activity, thereby accounting for the decrease or increase in cancer drug accumulation in resistant cells. We conclude that flavonoids often ingested by cancer patients may have different effects on anticancer drugs and that these findings should be considered in designing future combination treatments for cancer patients.
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PMID:Modulation of P-glycoprotein-mediated anticancer drug accumulation, cytotoxicity, and ATPase activity by flavonoid interactions. 2146 89

Gingival enlargement is common among patients and can be caused by a variety of etiological factors. The most common reason is poor oral hygiene and high bacterial load that leads to gingival inflammation and enlargement. Other implicated factors include systemic drugs, such as Phenytoin (Dilantin) taken by epileptic patients, Calcium Channel Blockers such as Nifedipine (Procardia) and Verapamil (Calan) for the treatment of hypertension, arrhythmia and angina. Another class of medication associated with gingival enlargement is immunosuppressive agents given to organ-transplant patients to prevent rejection of the new element, such as Cyclosporine. Some enlargements could be associated with other conditions such as puberty, pregnancy or diabetes or be a symptom of a systemic disease (leukemia, Wegener's granulomatosis or sarcoidosis). In rare cases the cause for the enlargement is genetic and termed Hereditary Gingival Fibromatosis (HGF). HGF is a genetic disorder characterized by a progressive enlargement of the gingiva. Histologically, the gingiva is characterized by an accumulation of dense fibrous connective tissue. This is believed to be due to an imbalance between synthesis and degradation of extracellular matrix composed mainly of collagen molecules or due to an alteration in fibroblast proliferation. Different pathogenic mechanisms have been proposed and examined over the years but no precise process has been identified. The main objective of this paper is to discuss this genetic anomaly and support it with clinical cases of a mother and her two children. It will focus on the clinical and histologic characteristics of HGF as well as known biologic and genetic features and treatment modalities.
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PMID:Gummy smile: could it be genetic? Hereditary gingival fibromatosis. 2334 94


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