Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increasing evidence suggests that P-glycoprotein (Pgp) expression can mediate drug resistance in refractory breast cancer. We studied 33 patients with refractory breast cancer enrolled in a pilot study of oral amiodarone as a Pgp antagonist given in combination with infusional doxorubicin or vinblastine. Whenever possible, tumors were biopsied and Pgp expression was assayed. Patients received either 60 mg/m2 doxorubicin over 96 h or 8.5 mg/m2 vinblastine over 120 h by continuous intravenous infusion. Beginning with the second cycle of chemotherapy, 600-800 mg amiodarone was given orally each day. Patients who experienced toxicity due to amiodarone but were responding to chemotherapy were placed on quinidine. Partial responses were observed in 9 of 33 patients on study and were sometimes observed after the first cycle of chemotherapy, before amiodarone was given, suggesting that some patients may have responded to treatment because of the infusional schedule. Toxicities were primarily the known side effects of the antineoplastic agents and of amiodarone. The major amiodarone toxicity was gastrointestinal, with nausea, vomiting, anorexia, or diarrhea being noted in 21 patients. Biopsy samples were obtained from 29 patients and in 21 cases, viable tumor tissue was present and the results were interpretable. Of the 21 samples, 9 had Pgp expression as determined by immunohistochemical staining; 12 were considered negative. The presence of Pgp expression was associated with an acceleration of the time to treatment failure. Whereas normal-tissue toxicities related to the combination of a Pgp antagonist with chemotherapy were not observed, amiodarone was associated with too many untoward effects to be utilized as a drug resistance-reversing agent.
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PMID:A pilot study of amiodarone with infusional doxorubicin or vinblastine in refractory breast cancer. 788 54

We used a series of P-glycoprotein (P-gp) expressing multidrug-resistant (MDR) cells, developed from human breast cancer MCF-7 cells by exposure to Adriamycin, to investigate the effects of flavonoids on P-gp-mediated efflux mechanisms for chemical carcinogens. We previously showed that MDR cells derived from exposure to Adriamycin are cross-resistant to a chemical carcinogen, benzo(a)pyrene, due to its cellular efflux by the P-gp-mediated putative drug efflux pump. Our current studies extended this observation to another polycyclic aromatic hydrocarbon, 7,12-dimethylbenz(a)anthracene, known to induce mammary tumors in animals. In our attempt to find naturally occurring dietary compounds which may stimulate the P-gp-mediated efflux of carcinogens, we found that certain flavonols, kaempferol, quercetin, and galangin, are potent stimulators of the P-gp-mediated efflux of 7,12-dimethylbenz(a)-anthracene. The increased efflux decreased the cellular burden of 7,12-dimethylbenz(a)anthracene. Since these flavonol compounds are widely distributed in fruits and vegetables, their stimulatory effect on P-gp may be a mechanism relevant to carcinogenesis and the observed lowered cancer risk in humans with higher dietary intake of fruits and vegetables.
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PMID:Flavonol-stimulated efflux of 7,12-dimethylbenz(a)anthracene in multidrug-resistant breast cancer cells. 790 98

P-glycoprotein-associated Cl- conductance is activated by cell swelling; the ensuing Cl- efflux is thought to contribute to cell volume regulation. We tested this hypothesis in human breast cancer cells transfected with human mdr1 complementary DNA, which display P-glycoprotein-associated, swelling-activated Cl- currents. The Cl- electrochemical driving force favors Cl- efflux, but there was no appreciable Cl- loss or regulatory volume decrease (both assessed with fluorescent dyes) during the exposure to hyposmotic solution. Calculations indicate that the swelling-activated Cl- current is insufficient to cause a significant Cl- efflux. Hence, regulatory volume decrease is not a function of P-glycoprotein.
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PMID:P-glycoprotein-associated Cl- currents are activated by cell swelling but do not contribute to cell volume regulation. 790 83

An MCF-7 human breast cancer line variant (MCF-7/MPA), resistant to medroxyprogesterone-acetate (MPA), was obtained by continuous exposure in vitro to the drug. MCF-7/MPA cells were grown in the presence of 12.5 x 10(-6) M MPA and were selected by increasing the concentration of the drug in the growth medium in a stepwise manner from 0.025 x 10(-6) M up to 12.5 x 10(-6) M. Comparative studies of cellular morphology, cytosolic steroid receptor content and P-Glycoprotein expression were performed on both MCF-7 parental line and MCF-7/MPA variant. MCF-7/MPA cells, when compared to the parental line, exhibit a different morphology in terms of membrane alterations, reduced content of cytosolic progesterone receptor, increased expression of P-glycoprotein along with reduction of Doxorubicin (Dx) activity on the growth of MCF-7/MPA resistant cells.
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PMID:Morphological and biochemical features of a medroxyprogesterone acetate (MPA)-resistant MCF-7 breast cancer cell line. 790 20

Paclitaxel (Taxol) is a new cytotoxic agent with considerable activity in phase II studies on metastatic breast cancer. Paclitaxel for clinical use is dissolved in the solvents cremophor EL and ethanol. In this study, we added paclitaxel, formulated either in cremophor EL and ethanol or only in ethanol, in increasing concentrations to two parental human breast cancer cell lines (ZR 75-1 and HS 578T) and their corresponding sublines with acquired doxorubicin resistance and P-glycoprotein expression. Paclitaxel dissolved either in ethanol or ethanol plus cremophor EL, resulted in steep and almost identical dose-response curves for the parental lines ZR 75-1 and HS 578T, respectively, independent of the solvent used. When paclitaxel was formulated only in ethanol the effects on the corresponding doxorubicin-resistant sublines were significantly reduced compared with paclitaxel dissolved in ethanol plus cremophor EL. These effects by cremophor EL may partly explain some of the antitumoral effects observed by paclitaxel in anthracycline failing patients.
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PMID:Paclitaxel-induced cytotoxicity--the effects of cremophor EL (castor oil) on two human breast cancer cell lines with acquired multidrug resistant phenotype and induced expression of the permeability glycoprotein. 791 8

This study demonstrates that the flavonoid quercetin (Q), a plant-derived compound with low toxicity in vivo, greatly potentiates the growth-inhibitory activity of Adriamycin (ADR) on MCF-7 ADR-resistant human breast cancer cells. The effect of Q was dose-dependent at concentrations ranging between 1 and 10 microM. Since ADR resistance in these cells is associated with the expression of high levels of P-glycoprotein (Pgp), we evaluated the effect of Q and related flavonoids of Pgp activity in cytofluorographic efflux experiments with the fluorescent dye rhodamine 123 (Rh 123). Our results indicate that Q and 3-OMe Q (3',4',7-trimethoxyquercetin) but not the 3-rhamnosylglucoside of Q (rutin) inhibit the Pgp pump-efflux activity in a dose-related manner. Moreover, 10 microM Q reduces the expression of the immunoreactive Pgp in MCF-7 ADR-resistant cells as evaluated by cytofluorimetric assay. In conclusion, these findings provide a further biological basis for the potential therapeutic application of Q as an anti-cancer drug either alone or in combination with ADR in multidrug-resistant breast tumor cells.
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PMID:Quercetin potentiates the effect of adriamycin in a multidrug-resistant MCF-7 human breast-cancer cell line: P-glycoprotein as a possible target. 763 87

The surface and intracellular expression of mdrI-P-glycoprotein in parental drug-sensitive human breast cancer cells (MCF-7) and their multidrug-resistant (MDR) variants has been studied by using the monoclonal antibodies (MAbs) MM4.17 and MRK-16, which recognize 2 different epitopes of the drug efflux pump molecule. Fluorescence microscopic observations showed that P-glycoprotein, in addition to being located at the cell surface, can also be found in the Golgi apparatus of resistant cells. To confirm this finding, Golgi apparatus and P-glycoprotein were double-labelled with wheat-germ agglutinin (WGA) and MAb MM4.17. Laser scanning confocal microscopy indicated that, in MDR cells, Adriamycin mainly accumulated cytoplasmically in a perinuclear region. This accumulation proved to be modulated by pre-treatment with verapamil or ATP depletion. Moreover, the vital staining of Adriamycin-treated MDR cells, performed with the fluorescent lipid N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]- 6-aminocaproyl sphingosine (C6-NBD-ceramide), revealed that the anthracyclinic antibiotic was located in the Golgi apparatus. All these results indicate that the drug transporter is located in the Golgi apparatus, in which Adriamycin molecules also accumulate.
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PMID:P-glycoprotein expression in the Golgi apparatus of multidrug-resistant cells. 798 20

Multidrug resistance (MDR) corresponds to the cross-over resistance of tumour cells to structurally unrelated cytotoxic chemotherapeutic drugs. One of the mechanisms causing this resistance is the enhanced expression of a transmembrane drug efflux pump P-glycoprotein (P-170). Reversal of P-glycoprotein-associated MDR has received much attention in recent years. In experimental cell lines, P-170 and the glutathione redox cycle seem to contribute to this phenomenon; P-170 may be inactivated by calcium and calmodulin antagonists and the glutathione redox cycle altered by buthionine sulphoximine (BSO). Treatment of human MCF-7 breast cancer cells with chemosensitizers (CS), such as verapamil, trifluoperazine or BSO, for 72 hr resulted in an enhanced sensitization of cells to Adriamycin, trifluoperazine being the most potent compound in the reversion of chemoresistance. In these Adriamycin sensitive or resistant cells, treated or not by the CS, the possible role of calcium and cyclic adenosine monophosphate (cAMP) in mediating the reversion of chemoresistance to Adriamycin was investigated. It was found that intracellular calcium was approximately 2-fold higher in resistant than in sensitive cells, the opposite was true for cAMP. Modifications in calcium and cAMP levels were observed in MCF-7 resistant cells after treatment with verapamil and BSO; trifluoperazine had no effect on these two parameters. These results seemed to rule out any implication of calcium and cAMP levels in the contribution of these three chemosensitizers in the mechanisms of reversion of chemoresistance to Adriamycin.
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PMID:Comparative study of intracellular calcium and adenosine 3',5'-cyclic monophosphate levels in human breast carcinoma cells sensitive or resistant to Adriamycin: contribution to reversion of chemoresistance. 808 Apr 43

The multidrug resistance (MDR) phenotype induces cross-resistance to many chemotherapeutic agents in cancer cells. Protein kinase C (PKC) has been implicated in the regulation of the MDR phenotype. In order to determine the role of specific PKC isoenzymes in regulating the MDR phenotype, the expression and activity of PKC isoenzymes in the human breast cancer cell line, MCF-7-WT, and an MDR subline, MCF-7-MDR, were examined. The MDR phenotype was associated with a 10-fold increase in calcium-dependent PKC activity as well as a 10-fold decrease in calcium-independent activity was due to a selective increase in the activity was due to a selective increase in the expression of PKC alpha as determined by Western blot analysis and hydroxylapatite chromatography. This increase in expression of PKC alpha was regulated at the message level as demonstrated by Northern blot analysis. The decrease in calcium-independent activity was caused by a decrease in the expression of PCK delta and epsilon. The significance of the increase in PKC alpha expression was then demonstrated by a commensurate 11-fold increase in the basal and stimulated phosphorylation of the myristolated alanine-rich C kinase substrate. Phosphorylation of P-glycoprotein, the cellular mediator of the MDR phenotype, was increased > 20-fold in the unstimulated MCF-7-MDR cell line and its phosphorylation was further increased 2-fold in response to phorbol 12-myristate 13-acetate. These changes paralleled the increases in P-glycoprotein pump function and the MDR phenotype underscoring the role for PKC alpha in regulating P-glycoprotein phosphorylation and function.
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PMID:Selective regulation of expression of protein kinase C (PKC) isoenzymes in multidrug-resistant MCF-7 cells. Functional significance of enhanced expression of PKC alpha. 809 47

In our efforts to identify clinically effective drugs for reversing multidrug resistance (MDR) mediated by P-glycoprotein, we tested terfenadine for anti-MDR activity because it appeared to sensitize a patient to doxorubicin and because it met structural requirements defined for this activity. Terfenadine sensitized MCF-7/ADR human breast cancer cells and L1210/VMDRC.06 murine leukemia cells to doxorubicin. At concentrations < or = 10 microM, terfenadine decreased the IC50 to doxorubicin by up to 25-fold against MCF-7/ADR cells and completely restored sensitivity to L1210/VMDRC.06 cells. The drug had no effect on the sensitive, parental cell lines and enhanced activity of other drugs affected by the MDR phenotype. Terfenadine was as potent as trans-flupenthixol, one of the most active modulators of MDR. The mechanism of action of terfenadine appeared to be due to inhibition of the function of P-glycoprotein since it augmented the accumulation of doxorubicin and inhibited the efflux of rhodamine 123 from MDR lines but had no effect on drug accumulation or efflux in sensitive cells. Terfenadine displaced azidopine from P-glycoprotein, but at concentrations higher than expected based on its overall potency. Since terfenadine is clinically available, has numerous structural derivatives available for study, and has a relatively low toxicity profile, this drug and drugs of its class should be evaluated for future clinical trials.
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PMID:Terfenadine (Seldane): a new drug for restoring sensitivity to multidrug resistant cancer cells. 809 15


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