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)

The new nonimmunosuppressive cyclosporin analogue, SDZ PSC 833, is a very potent multidrug-resistance modifier. In vitro, it was shown to be at least 10-fold more active than cyclosporin A (Sandimmune), itself more active than verapamil, on most P-glycoprotein-expressing multidrug-resistant (MDR) tumor cell lines. In vivo, SDZ PSC 833 was tested in a few protocols of combined therapy with either Vinca alkaloids or doxorubicin as anticancer drugs, using the homologous tumor-host system (P388 cells of DBA/2 origin grafted into DBA/2 or B6D2F1 mice). Although these MDR-P388 tumor cells belong to a highly resistant variant that in vitro required about 150-fold more anticancer drug for 50% cell growth inhibition than the parental P388 cells, significant prolongation of survival times of the MDR-P388 tumor-bearing mice was obtained when treated with a combination of SDZ PSC 833 p.o. were otherwise ineffective doses of anticancer drugs given i.p. This chemosensitizing effect of SDZ PSC 833 was dose-dependent and was most effective in a protocol combining administration of SDZ PSC 833 p.o. 4 h before a doxorubicin i.p. injection: in comparison with the survival of MDR-P388 tumor-bearing mice treated with the anticancer drug alone, the pretreatment with SDZ PSC 833 at 25 and 50 mg/kg gave 2- to 3-fold increases of survival times. Since the MDR-P388 tumor cells used in our studies belong to a highly resistant variant, with a much higher degree of drug resistance than the one known to occur in cancer patients, SDZ PSC 833 appears to be a very promising chemosensitizer.
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PMID:In vivo circumvention of P-glycoprotein-mediated multidrug resistance of tumor cells with SDZ PSC 833. 167 13

It is believed that P-glycoprotein (P-gp) is an energy-dependent drug efflux pump responsible for decreased drug accumulation in multidrug resistant (MDR) cells. In this study, we investigated whether azidopine, a photoactive dihydropyridine calcium channel blocker, is transported by P-gp in MDR Chinese hamster lung cells, DC-3F/VCRd-5L, and whether its binding site(s) on P-gp are distinct from those of Vinca alkaloids and cyclosporins. The efflux of azidopine from MDR cells was energy-dependent and inhibited by the cytotoxic agent vinblastine (VBL). Cyclosporin A (CsA), a modulator of MDR, also increased azidopine accumulation in MDR cells by decreasing the energy-dependent efflux of azidopine. P-gp in these cells was the only protein specifically bound to [3H]azidopine in photoaffinity experiments. The specific photoaffinity labeling of P-gp by [3H]azidopine was inhibited by CsA, SDZ 33-243, nonradioactive azidopine, and VBL with median concentrations (IC50) of 0.5, 0.62, 1.7, and 25 microM, respectively. The equilibrium binding of azidopine to plasma membranes of MDR variant DC-3F/VCRd-5L cells showed a single class of specific binding sites having a dissociation constant of 1.20 microM and a maximum binding capacity of 4.47 nmol/mg of protein. Kinetic analysis indicated that the inhibitory effect of VBL and CsA on azidopine binding to plasma membranes of MDR cells was noncompetitive, indicating that azidopine binds to P-gp at a binding site(s) different from the binding site(s) of these drugs.
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PMID:Azidopine noncompetitively interacts with vinblastine and cyclosporin A binding to P-glycoprotein in multidrug resistant cells. 167 34

Induction of P-glycoprotein-related multi-drug-resistance (MDR) has been shown in normal and malignant tissues to result from environmental stresses such as heat shock, exposure to carcinogens or X-ray irradiation. To identify conditions under which MDR is enhanced during anti-neoplastic chemotherapy, a cell line showing low-level intrinsic MDR was investigated. In the pleural mesothelioma cell line, PXF1118, less than 1% of cells expressed P-glycoprotein (P-gp), as shown by immunocytochemical staining with monoclonal antibody (MAb) MRK16. Exposure of PXF1118 to vincristine, vindesine, vinblastine or doxorubicin for 2-3 weeks led to an increase in the MDR cell fraction of up to 15-28% during 2 to 3 weeks. For doxorubicin and vindesine, dose-dependence was observed: drug concentrations not capable of eliciting cytotoxicity failed to induce significant P-gp expression. Nutrient starvation in aging medium, exposure to activated cyclophosphamide (even at high concentrations) or cisplatin caused only negligible MDR induction. After exposure to vindesine for 6 weeks, tumor colonies exhibited highly enhanced resistance to Vinca alkaloids, doxorubicin, etoposide and dacarbacine, whereas their sensitivity to mitomycin, activated cyclophosphamide or cisplatin remained unchanged. As determined by [3H]-thymidine uptake and proliferation antigen expression, induction of MDR phenotype was observed at minimal proliferative activity with no change in cell count during exposure to anti-cancer drugs, thus suggesting that the drug treatments changed the phenotype of the cells rather than selecting for a resistant sub-population. In addition, changes in cell differentiation were observed during MDR induction. Induction of P-gp during exposure to anti-cancer drugs thus provides a model for MDR development during initially successful chemotherapy. of P-gp during exposure to anti-cancer drugs thus provides
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PMID:Induction of multiple-drug resistance during anti-neoplastic chemotherapy in vitro. 191 65

A series of CCRF-CEM sublines selected for extreme resistance to methotrexate has been shown previously to exhibit cross resistance to a number of agents belonging to the multidrug resistance phenotype. The mechanism(s) underlying resistance to vincristine, vinblastine and actinomycin D in the most resistant subline (CEM/MTX R3) has now been investigated. Efflux of [3H]vincristine was more rapid in CEM/MTX R3 than in either CCRF-CEM cells or a methotrexate-resistant subline not refractory to Vinca alkaloids. In addition, verapamil completely reversed resistance to vincristine, vinblastine and actinomycin D in the CEM/MTX R3 cells. While these results are suggestive of P-glycoprotein-mediated multidrug resistance, Northern analysis revealed no detectable expression of the mdr 1/gene in CEM/MTX R3 cells. Likewise, karyotypic analysis of the resistant subline, while revealing certain clonal abnormalities, provided no evidence of alteration in the mdr 1/gene locus on chromosome 7. The data suggest therefore the operation, in these cells, of a novel mechanism of resistance.
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PMID:Phenotypic and cytogenetic analysis of atypical multidrug resistance in human leukaemic cells selected with methotrexate at high concentration. 197 35

The interaction of etoposide (VP-16), Vinca alkaloids, and verapamil with the P-glycoprotein (P-gp) was studied in human breast (MCF-7) and Chinese hamster lung (DC3F) cell lines and the corresponding multidrug-resistant MCF-7/ADR and DC3F/ADX tumor cell lines, selected for resistance to Adriamycin and actinomycin D, respectively, and overexpressing P-gp. Verapamil (10 microM) markedly reversed resistance to vincristine (11-fold in DC3F/ADX and 125-fold in MCF-7/ADR; 1-hr exposure), but it had a very modest effect on resistance to VP-16 (3- to 4-fold; 1-hr exposure). Resistant cells accumulated 2- to 4-fold less VP-16 and vincristine than the parental cell lines. Verapamil (10 microM) significantly increased accumulation and retention of vincristine, but not of VP-16, in resistant cell lines. Photoaffinity labeling of resistant cell lines with radioactive analogs of verapamil [N(p-azido-3-125I-salicyl)-N'-beta-aminoethylverapamil (NASVP)] and vinblastine[N-(p-azido-3-125I-salicyl)-N'-beta-aminoethylvindesine (NASV)] showed distinctly labeled P-gp bands in both resistant cell lines, compared with wild-type cells. Excess nonradioactive vinblastine or verapamil effectively competed with the P-gp photolabeling by either NASVP or NASV, with IC50 levels of 0.6 and 10 microM, respectively. In contrast, nonradioactive VP-16 was 100- to 500-fold less potent than vinblastine in competing with P-gp photolabeling, suggesting that VP-16 has significantly lower affinity for P-gp than Vinca alkaloids have. Taken together, our data indicate that P-gp glycoprotein by itself may not be important in the transport/efflux of VP-16 and, thus, in the mechanism of resistance to VP-16 in these cells.
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PMID:P-glycoprotein-independent mechanism of resistance to VP-16 in multidrug-resistant tumor cell lines: pharmacokinetic and photoaffinity labeling studies. 197 71

The mechanism of reversal of resistance to Vinca alkaloids by cyclosporins is unclear. We investigated the molecular mechanism of reversal of Vinca alkaloid resistance by cyclosporin A (CsA) and its nonimmunosuppressive analog O-acetyl C9(1) CsA (SDZ 33-243) in multidrug resistant DC-3F/VCRd-5L Chinese hamster cells. CsA at 3 microM increased vincristine (VCR) sensitivity and almost totally reversed VCR resistance. SDZ 33-243 at 1 microM reduced the IC50 for VCR in resistant cells from 62.0 to 0.00062 microM. CsA and SDZ 33-243 at 10 microM increased [3H]vinblastine (VBL) accumulation in DC-3F/VCRd-5L cells by 27- and 22-fold, respectively. At 10 microM, these compounds also increased [3H]VCR accumulation by 3.5- and 4.0-fold, respectively. [3H]VCR uptake by membrane vesicles from DC-3F/VCRd-5L cells showed high and low affinity components with Michaelis-Menten kinetics, and apparent Km values were 0.140 +/- 0.0523 and 24.8 +/- 6.67 microM, respectively. Kinetic analysis of [3H]VCR uptake in membrane vesicles in the presence of 0.2 microM CsA revealed that CsA competitively inhibited the high affinity [3H]VCR uptake with an apparent inhibition constant (Ki) of 0.126 +/- 0.0173 microM. In addition, CsA and SDZ 33-243 inhibited VBL photoaffinity labeling of P-glycoprotein in a dose-dependent manner, with half-maximum inhibition at 0.5 and 0.4 microM, respectively, compared with that of VBL at 0.6 microM. These data confirm that cyclosporins modulate Vinca alkaloid resistance at least partially through interaction with P-glycoprotein.
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PMID:Competitive interaction of cyclosporins with the Vinca alkaloid-binding site of P-glycoprotein in multidrug-resistant cells. 197 13

UCLA-P3 human lung adenocarcinoma cells were grown in nude mice and given repetitive treatments of a monoclonal antibody-Vinca alkaloid immunoconjugate. Although this therapy resulted in a greater than 4-fold reduction in mean tumor mass of the established tumors, some animals experienced a reinitiation of tumor growth after cessation of conjugate treatment. Two such animals were treated again with high doses of monoclonal antibody-Vinca but one of the tumors was no longer regressed by the drug conjugate. The tumor was excised, enzymatically dissociated, and grown in tissue culture. Cultured cells were reimplanted in nude mice and subjected to further therapy with a monoclonal antibody-Vinca conjugate. The resulting tumors were also refractory to the immunoconjugate therapy. This cycle was repeated for a total of three times and resulted in the serial in vivo selection of three conjugate resistant variants. The mechanism responsible for the in vivo resistance of human tumor cells to the monoclonal antibody-Vinca immunoconjugate is unknown but does not appear to involve antigen modulation, altered tumor cell growth rate, or an apparent decrease in tumor targeting in vivo. The resistance was also not accompanied by any detectable elevation in multidrug resistance 1 mRNA or P-glycoprotein expression. Significantly, the resistance pattern was observed only in vivo and was not maintained by cells grown in vitro.
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PMID:In vivo selection of human tumor cells resistant to monoclonal antibody-Vinca alkaloid immunoconjugates. 197 47

The MDR1 gene encodes an Mr 170,000 energy-dependent drug efflux pump (P-glycoprotein) which transports hydrophobic agents such as Adriamycin, colchicine, the Vinca alkaloids, and actinomycin D out of cells. Increased expression of the mdr gene has been observed in preneoplastic and neoplastic carcinogen-induced rat liver nodules as well as in regenerating rat liver, suggesting that the mdr gene is regulated in response to liver injury. To determine whether the increased levels of mdr mRNA seen in regenerating liver are the result of an increased rate of transcription or a posttranscriptional event, nuclear run-on assays were performed on nuclei isolated from regenerating rat livers 4-72 h after partial hepatectomy. Whereas Northern blot analysis of regenerating rat liver demonstrated a greater than 20-fold increase in mdr mRNA levels, there was little or no increase in mdr gene transcription as measured by nuclear run-on analyses. beta-Actin and metallothionein gene transcription levels, known to increase transiently in regenerating liver, both showed increased nuclear run-on activity 4 h posthepatectomy, indicating that the nuclei were functional. Failure to demonstrate a substantial increase in mdr gene transcription suggests that the observed increase in mdr mRNA levels may result from a posttranscriptional event such as message stabilization. The sequence of the 3' noncoding region of the MDR1 gene shares strong homology with other unstable mRNAs, suggesting that RNA stabilization could account for the rise of mdr mRNA after partial hepatectomy.
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PMID:Regulation of the multidrug resistance gene in regenerating rat liver. 198 15

Resistance of tumors to a variety of chemotherapeutic agents presents a major problem in cancer treatment. Resistance to such agents as doxorubicin, Vinca alkaloids, and actinomycin D can be acquired by tumor cells after treatment with a single drug. The gene responsible for multidrug resistance, termed mdr1, encodes a membrane glycoprotein (P-glycoprotein) that acts as a pump to transport various cytotoxic agents including various xenobiotics out of the cell. The amount of P-glycoprotein expression has been measured in tumor samples and was found to be elevated in intrinsically drug-resistant cancers of the colon, kidney, and adrenal as well as in some tumors that acquired drug resistance after chemotherapy. The protein was also found to be elevated in cells treated with xenobiotics. P-glycoprotein has been shown to bind anticancer drugs and several resistance-reversing agents including calcium channel blockers, and to be an ATPase. We recently reconstituted the purified P-glycoprotein into artificial liposomes. Reconstituted P-glycoprotein showed ATPase activity, ATP-dependent drug-transport activity, and calcium channel blocker-binding activity. This model provides many advantages for studies of the biochemical functions of P-glycoprotein. In addition to these basic interests, the protein is of considerable interest as a target for cancer chemotherapy because it appears to be involved in both acquired multidrug resistance and intrinsic drug resistance in human cancer. The selective killing of tumor cells expressing P-glycoprotein could be very important in future cancer therapy.
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PMID:Multidrug resistance: a transport system of antitumor agents and xenobiotics. 198 21

Phenoxazine and seven other structurally related compounds were investigated to determine whether they would increase accumulation of Vinca alkaloids in multidrug-resistant (MDR) GC3/C1 (human colon adenocarcinoma) and KB-ChR-8-5 (HeLa variant) cell lines. Among eight compounds examined, phenoxazine caused greater accumulations of vincristine (VCR) and vinblastine (VLB) than the other chemosensitizers. The structure-activity relationship of these compounds for anti-MDR activity suggested an ideal tricyclic ring structure with a basic nitrogen atom at position 10 for modulating the accumulation of Vinca alkaloids. Addition of oxygen to position 5 of the tricyclic ring system further increased the activity, implying that a highly electronegative element with one, or more, lone pair of electrons in the nucleus opposite to heterocyclic nitrogen was a requirement for better anti-MDR activity. The relationship between the concentration of phenoxazine and the potentiation of Vinca alkaloid accumulation in comparison to verapamil was examined. For VCR in GC3/C1 cells, maximal modulation indices were: for verapamil, 1.8; phenoxazine, 8.6; and for VLB, 1.3 for verapamil compared to 3.3 for phenoxazine. In KB-ChR-8-5 cells, for VCR the maximal modulating index values were 9.0 and 4.3, respectively, and for phenoxazine and verapamil and for VLB were 5.0 and 3.7, respectively. Accumulations of VLB in GC3/C1 cells were similar in the presence of 1 microM phenoxazine or 10 mM sodium azide plus 10 mM 2-deoxyglucose. The effects of verapamil and phenoxazine on the accumulation of Vinca alkaloid were additive. Further, phenoxazine decreased the efflux of VLB by 30% in KB-ChR-8-5 cell line and 10% in GC3/C1 cells. In addition to enhancing the cytotoxicities of VCR and VLB, phenoxazine competed relatively weakly for binding to P-glycoprotein with [3H]azidopine and moderately with [3H]azidoverapamil, at equal concentrations, suggesting that the multidrug transporter may be the primary target for phenoxazine.
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PMID:Structural determinants of phenoxazine type compounds required to modulate the accumulation of vinblastine and vincristine in multidrug-resistant cell lines. 237 85


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