Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the ability of cyclosporin A (CsA) and a non-immunosuppressive analogue, O-acetyl cyclosporin A (OACsA, B3-243) to inhibit the growth of human lung cancer cells in vitro. Using continuous drug exposure and the MTT colorimetric assay to determine cell growth we found that CsA produced partial growth inhibition at doses ranging from 0.5 to 3.0 micrograms ml-1 (0.4-2.4 microM). At progressively higher doses, complete growth inhibition and in situ cell lysis were seen. The P-glycoprotein expressing multidrug resistant (MDR) variant H69/LX4 of the small cell line H69/P was less sensitive to cyclosporins than the parent line, but this was not true of the non-P-glycoprotein expressing MDR variants of large cell line COR-L23 or adenocarcinoma line MOR. Sensitivity to OACsA was approximately 2-fold higher than that to CsA in most of the lines although not in the most sensitive line, COR-L88. Even in COR-L88, exposed to CsA or OACsA for 24 h, clonogenic cell survival was reduced only to 50%. There was no reduction in polyamine content of COR-L23 or COR-L88 cells following 48 h of exposure to CsA or OACsA. The effects on cell growth could not be inhibited by the addition of exogenous putrescine, nor could they be enhanced by the addition of alpha-difluoromethylorthinine. It does not appear therefore that inhibition of polyamine synthesis is the basis of the observed growth inhibition.
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PMID:Effects of cyclosporin A and a non-immunosuppressive analogue, O-acetyl cyclosporin A, upon the growth of parent and multidrug resistant human lung cancer cells in vitro. 131 90

Anthracyclines possessing either a 9-alkyl modification in the A-ring of the tetracyclic aglycone and/or specific changes to the amino sugar moiety retain effective cytotoxic activity against multidrug resistant (MDR) cell lines. To obtain a better understanding of the structural features responsible for this potentially valuable behaviour, we used the MTT tetrazolium dye reduction assay to calculate resistance factors (RF = the ratio of ID50 for the drug-resistant line to that for the parental line) for the EMT6/P mouse mammary tumour and its MDR variant EMT6/AR1.0, and the H69/P human small cell lung cancer line and its MDR counterpart H69/LX4. Both MDR lines exhibit marked resistance to doxorubicin, MDR 1 gene amplification, hyperexpression of the membrane P-glycoprotein and reduced drug accumulation. RF values for doxorubicin were 34 and 131 in the EMT6 and H69 cell line pairs, respectively. The 9-alkyl-substituted anthracyclines were confirmed as having RF values 9- to 15-fold lower than those for doxorubicin. The 9-ethyl analogues Ro 31-1966 (RF for EMT6 2.2, RF for H69 4.7) and Ro 31-1749 (RF for EMT6 3.9, RF for H69 9.5) were superior to the previously studied 9-methyl analogue Ro 31-1215 (RF for EMT6 8.1 RF for H69 12.4). A clear trend for RF values to decrease with increasing 9-alkyl chain length was also noted in the structurally more complex aclacinomycin series. For example, 13-methyl-aclacinomycin (RF for EMT6 1.0, RF for H69 2.2) featuring a 9-isopropyl moiety was superior to the 9-alkyl-containing aclacinomycin A (RF for EMT6 4.7, RF for H69 5.8), and this was in turn more effective than the 9-methyl analogue sulfurmycin A (RF for EMT6 6.4, RF for H69 14.2). The trisaccharide moiety was not an essential feature for activity against MDR lines in the aclacinomycins, as shown by the low RF value with aklavine (RF for EMT6 2.1, RF for H69 2.5). However, a small change in one of the sugar moieties of aclacinomycin A, as in marcellomycin, resulted in a considerable increase in RF values (RF for EMT6 18.5, RF for H69 25.3). The complex anthracyclines AD 32 (RF for EMT6 6.5, RF for H69 11.7) and particularly tetrahydropyranyl-doxorubicin (RF for EMT6 1.4, RF for H69 3.2) were effective against MDR lines.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Further examination of 9-alkyl- and sugar-modified anthracyclines in the circumvention of multidrug resistance. 133 31

A cell line (GZL-8) was established by cloning from ascitic fluid of an untreated ovarian carcinoma patient. The cells grew rapidly, accumulated lipids and showed chromosomal alterations. One of the marker chromosomes showed characteristics of a Y-like chromosome. This unusual finding was confirmed by DNA hybridisation using specific probes to the Y chromosome. The cells stained with fluorescent antibodies to desmoplakin and cytokeratins 8, 18, 19, and weakly with vimentin but not with desmin. The presence of epithelial membrane antigen, human milk fat globulin, alpha-lactalbumin, alpha-fetoprotein, placental alkaline phosphatase and oestrogen receptor-related antigen was demonstrated by indirect immunoperoxidase staining, but no CA-125 antigen could be detected. The cells showed positive reaction with antibodies to P-glycoprotein. The function of the P-glycoprotein transport system was demonstrated by the rhodamine-123 release test. The cells were initially responsive to doxorubicin, and to high concentrations of cisplatin. Growth inhibition by doxorubicin, especially at low doses was enhanced by the addition of verapamil or tamoxifen. This was shown by the soft agar clonogenic assay, by direct cell counting and by the MTT reducing test. Our results show that combination between drug and sensitivity modulators may be of potential clinical value in ovarian cancer.
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PMID:A cell line with unusual characteristics from an ovarian carcinoma patient: modulation of sensitivity to antitumour drugs. 134 52

We evaluated the multidrug resistance (MDR)-modulating effects of progesterone (PRG) and an orally active, structurally related compound, megestrol acetate (MA), in several MDR human cell lines. At 100 microM, both steroids inhibited the binding of a Vinca alkaloid photoaffinity analog to P-glycoprotein (P-gp) in MDR human neuroblastic SH-SY5Y/VCR cells [which show greater than 1500-fold resistance to vincristine (VCR) in the tetrazolium dye (MTT) assay]. However, 100 microM MA markedly enhanced the binding of [3H]-azidopine to P-gp in both SH-SY5Y/VCR cells and the MDR human epidermoid KB-GSV2 cell line (which displays 250-fold resistance to VCR in the MTT assay). PRG had little effect on the binding of [3H]-azidopine to P-gp. MA at low doses was more effective than PRG in sensitizing cells to VCR and enhancing their accumulation of [3H]-VCR. The highly resistant SH-SY5Y/VCR subline exhibited significant collateral sensitivity to both steroids. These data suggest that MA may be a clinically useful modulator of MDR.
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PMID:Megestrol acetate reverses multidrug resistance and interacts with P-glycoprotein. 134 73

Although cellular drug resistance is considered to be an important cause of the poor prognosis of children with relapsed acute lymphoblastic leukaemia (ALL), the knowledge of drug resistance in these patients is very limited. Different aspects of drug resistance were studied in 17 children with relapsed ALL. The in vitro sensitivity profile was determined using the MTT assay. Cells from relapsed children were significantly more resistant to 6-thioguanine, prednisolone, cytosine arabinoside, daunorubicin (DNR), mustine-HCl and mafosfamide but not to L-asparaginase and vincristine (VCR) than cells from 41 children with ALL at initial diagnosis. Some relapsed patients showed a general drug resistance while others were resistant to only 1-3 drugs. The relevance of the multidrug resistance (MDR) model was analysed: In all DNR- and VCR resistant cases a co-resistance to drugs not involved in the MDR model was found. P-glycoprotein was not detected in any of 28 untreated and 14 relapsed samples tested. VCR- and DNR accumulation in the most resistant cells were not lower than in sensitive cells. Resistance modifiers did not potentiate the cytotoxicity of VCR and DNR. We conclude that resistance to anthracyclines and vinca alkaloids in childhood relapsed ALL is not due to P-glycoprotein mediated MDR. Different types of drug resistance varying from a resistance to only one drug to a general chemoresistance, can be detected in children with relapsed ALL. VCR and L-asparaginase seemed to be only infrequently involved in drug resistance. Knowledge of drug resistance might lead to more effective and less toxic therapies for children with relapsed ALL.
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PMID:Different types of non-P-glycoprotein mediated multiple drug resistance in children with relapsed acute lymphoblastic leukaemia. 135 Feb 7

A 4-day colorimetric tetrazolium dye (MTT) assay was used to assess the cytotoxicity of adriamycin (ADM), vincristine (VCR), and idarubicin (IDA) in blasts isolated from 37 patients with newly diagnosed and pretreated acute myeloid leukemia (AML). The effect of verapamil (VRP) as a chemosensitizer was studied in relation to the expression of the membrane efflux pump P-glycoprotein (PGP) as determined by a semiquantitative flow-cytometric proceder. A slight positive correlation was found between the fraction of cells expressing PGP and the ID50 values for ADM and VCR, but not between cellular PGP content and sensitivity to IDA. The overall data showed no significant sensitization effect of VRP. However, in specimens with more than 10% cells expressing PGP, 2 microM VRP sensitized cells to ADM and VCR significantly. The median of sensitization ratios (SRs), i.e., the ratios of cytotoxic drug ID50 in the absence/presence of VRP, were 1.89 and 2.0, respectively. No sensitizing effect of VRP on the cytotoxicity of IDA was observed. Related to the clinical status, the median fraction of PGP-positive blasts was elevated fourfold in pretreated patients (n = 16) in comparison to patients with de novo AML (n = 19). No differences in ID50 values were observed between newly diagnosed and pretreated patients. However, SRs for ADM and VCR were higher in samples of pretreated patients compared with de novo AML. PGP-mediated cellular drug resistance may thus be circumvented in leukemic blasts by application of chemosensitizers or, potentially, alternative anthracyclines.
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PMID:Cytotoxicity of adriamycin, idarubicin, and vincristine in acute myeloid leukemia: chemosensitization by verapamil in relation to P-glycoprotein expression. 136 Aug 20

Thirty four patients with acute myeloid leukemia (AML) (30 de novo and 4 relapsed) were evaluated for P-glycoprotein (P-gp) expression, and in vitro chemosensitivity. The P-gp expression was evaluated by immunohistochemical method using JSB-1 monoclonal antibody and the results were visualized by peroxidase-antiperoxidase goat antimouse antibody and the in vitro chemosensitivity was measured by the semiautomated MTT colourimetric assay method. Depending upon the percent cells expressing P-gp and the intensity of P-gp staining, the samples were graded as absent, mild or strong for the relative P-gp expression, which was further correlated with the in vitro chemosensitivity and the clinical response of the tumors. Expression of P-gp was seen in 17 of the 30 de novo AML cases and all four relapse cases. Patients with no P-gp expression showed in vitro chemosensitivity while those with strong P-gp expression were resistant in vitro. Patients with mild P-gp expression showed varied chemosensitivity. P-gp expression correlated with clinical response to chemotherapy. Seven out of 11 patients with no P-gp achieved complete remission (C.R.). The other four died early in induction. Of five patients who expressed strong P-gp, four had resistant disease and the autopsy study of the remaining patient who died in induction revealed persistent disease. Of the 10 de novo AML patients who had mild P-gp expression, five achieved C.R. while one had resistant disease and four died in induction. All the four relapsed AML showed mild P-gp expression.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of the multidrug transporter P-glycoprotein and in vitro chemosensitivity: correlation with in vivo response to chemotherapy in acute myeloid leukemia. 168 90

The cephalosporins are a family of semisynthetic antibiotics, some of which have structural features associated with substrates for the multidrug transporter, P-glycoprotein. The activity of a series of six cephalosporins in reversing multidrug resistance (MDR) was examined in MDR variants (Dx5 cells) of the human sarcoma line MES-SA. Dx5 cells express high levels of the mdr1 gene product P-glycoprotein and are 25- to 30-fold resistant to doxorubicin (DOX), etoposide (VP-16), and vinblastine (VBL). Cytotoxicity was measured by the MTT assay. Cefoperazone (1.0 mM) was the most effective modulator of MDR, lowering the IC50 for VP-16 by 29-fold (29x), for VBL by 16x, and for DOX by 14x. Ceftriaxone at 1.0 mM produced 10x modulation of VP-16 cytotoxicity, 8x for DOX, and 2x for VBL. The reversal of resistance was concentration dependent, decreasing to 4x and 5x, respectively, for DOX with 0.25 mM cefoperazone and ceftriaxone. No modulation of cytotoxicity was observed in the parental MES-SA cells, which do not express mdr1. Cefazolin, cefotetan, cephradine, and ceftazidime were ineffective, producing less than 5x modulation of DOX at 1.0 mM. Among these cephalosporins, cefoperazone and ceftriaxone were the most highly protein bound in the media (30 and 52%), and the most lipid soluble, with octanol/water partitioning coefficients of -0.49 and -0.60. Varying the serum concentration in medium from 5 to 50% had less than a two-fold effect on the modulation of MDR by ceftriaxone. The ability to reverse MDR among these agents is associated with lipid solubility, high protein binding, a polycyclic planar geometry, and the presence of the piperazine group in cefoperazone. These data and the potential for achieving high tissue concentrations indicate that cefoperazone merits further study as a modulator of MDR.
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PMID:Reversal by cefoperazone of resistance to etoposide, doxorubicin, and vinblastine in multidrug resistant human sarcoma cells. 258 32

We reported earlier that human cervical carcinoma HeLa cells exposed to 30 fractions of 0.5 Gy gamma-rays became resistant to cisplatin, methotrexate and vincristine, but retained the same sensitivity to gamma-rays and ultraviolet light. The aim of this study was to examine whether a small number of gamma-ray fractions, with a lower daily dose, may also change the sensitivity of preirradiated cells to different cytotoxic drugs. Using the modified MTT staining procedure, we found that cells preirradiated with 5 or 10 daily fractions of only 0.17 Gy gamma-rays did not alter their sensitivity to mitomycin, cisplatin, methotrexate, 5-fluorouracil, etoposide and doxorubicin. However, 10 fractions of gamma-rays induced resistance to vincristine and vinblastine. Our immunocytochemical experiments using monoclonal antibody JSB-1 show that the plasma membrane P-glycoprotein is involved in the induced resistance to Vinca alkaloids.
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PMID:Low doses of gamma-rays can induce the expression of mdr gene. 751 68

Deoxyspergualin, a synthetic analogue of the immunosuppressive anti-tumour antibiotic spergualin, has been shown to possess potent in vitro and in vivo anti-tumour activity and is currently in the National Cancer Institute (NCI) decision network. Deoxyspergualin shows similarities in properties and mechanisms of action to the natural-product immunosuppressive agents cyclosporin A and FK506, each of which can act as a modifier of multidrug resistance. We therefore decided to examine the comparative activity of deoxyspergualin in parent and multidrug-resistant cells. Deoxyspergualin contains the polyamine spermidine within its structure. Bovine serum copper amine oxidase catalyses the oxidative deamination of spermidine to produce an aminoaldehyde, ammonia and hydrogen peroxide. These aminoaldehydes are believed to be responsible for the toxicity of polyamines in vitro in the presence of bovine serum. For this reason, all experiments were carried out in medium containing bovine serum and in medium containing horse serum (which is low in copper amine oxidase content). We used the tetrazolium (MTT) colorimetric assay to determine drug sensitivity and tritiated daunorubicin accumulation together with inhibition of azidopine binding to study specific mechanisms of resistance modulation. The murine cell lines EMT6/P and EMT6/AR1.0 and the human cell lines H69/P and H69/LX4 were, respectively, 32-, 32-, 372- and 483-fold more sensitive to spermidine and 175-, 133-, 321- and 444-fold more sensitive to spermine in the presence of calf serum than in the presence of horse serum. However, these large differential effects were not seen for deoxyspergualin. It appears that in the presence of horse serum, deoxyspergualin may exert its effect by a mechanism other than polyamine oxidation. Deoxyspergualin did not enhance the accumulation of [3H]-daunorubicin in EMT6/AR1.0 cells. Furthermore, deoxyspergualin (1-20 microM) did not restore the sensitivity of EMT6/AR1.0 or H69/LX4 cells to that of the parent lines. P-glycoprotein (Pgp) in membranes prepared from H69/LX4 cells was photo-affinity-labeled with [3H]-azidopine. Deoxyspergualin did not inhibit this labeling. Although deoxyspergualin appears to exert its immunosuppressive effect via a mechanism similar to that of cyclosporin A and FK506, it does not share their ability to modify Pgp-mediated multidrug resistance. However, its lack of cross-resistance and potent in vivo anti-tumour activity make deoxyspergualin a promising candidate for development as an anti-cancer agent.
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PMID:The activity of deoxyspergualin in multidrug-resistant cells. 755 42


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