Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The feasibility of combined studies on a cell-line panel and primary cultures of patient tumor cells in the preclinical evaluation of new anticancer drugs was evaluated in a study of the activity and cross-resistance pattern in vitro of the new semi-synthetic vinca alkaloid vinorelbine (Vrb). The activity of Vrb was investigated in ten cell lines representing different resistance mechanisms and in a total of 256 fresh human tumor samples, using the fluorometric microculture cytotoxicity assay (FMCA). Resistance to Vrb in the cell lines was associated with expression of the multidrug resistance-mediating P-glycoprotein and the multidrug resistance-associated protein (MRP) and by a recently described tubulin-associated mechanism, while the cell lines with topoisomerase II- and glutathion-associated resistance did not show decreased sensitivity to the drug. Cross-resistance to vincristine (Vcr) and other tubulin-active agents was high in cell lines as well as in patient cells. As with most commonly used anti-cancer drugs, Vrb was more active in hematological than in solid tumor samples. Among the solid tumors investigated, the highest in vitro response rates were observed in ovarian cancer (27%), sarcoma (25%), non-small cell lung cancer (21%) and bladder cancer (20%), while no response was observed in renal or colorectal cancer. Compared to Vcr, Vrb appeared to be slightly more active in solid tumors and slightly less active in hematological tumors. The results show that although Vrb displays a high degree of cross-resistance to Vcr and other tubulin-active drugs, some difference in the activity spectrum could be detected and that the drug is sensitive to multiple mechanisms of resistance. The results also suggest that leukemias, ovarian cancer, sarcoma and bladder cancer are possible further targets for Vrb. The combination of studies on a cell-line panel and patient tumor cells from a broad spectrum of diagnoses to evaluate a new drug seems feasible and may give information on the mechanism of action and target diagnoses for phase II trials.
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PMID:In vitro evaluation of new anticancer drugs, exemplified by vinorelbine, using the fluorometric microculture cytotoxicity assay on human tumor cell lines and patient biopsy cells. 941 16

The P-glycoprotein is an energy-dependent efflux pump capable of decreasing the intracellular concentration of a broad range of chemotherapeutic agents. [99mTc]Sestamibi, a P-glycoprotein transport substrate, is a sensitive probe of P-glycoprotein function both in vitro and in vivo. A human tumor model in nude mice was evaluated to determine whether [99mTc]Sestamibi could detect in vivo differences in P-glycoprotein expression and P-glycoprotein modulation by the reversal agent SDZ PSC 833. Differential [99mTc]Sestamibi accumulation based upon P-glycoprotein expression was demonstrated in xenografts in vivo. Dose-dependent inhibition of P-glycoprotein function was achieved with SDZ PSC 833. Administration of the reversal agent increased [99mTc]Sestamibi accumulation in the xenografts expressing P-glycoprotein. These observations show that [99mTc]Sestamibi as capable of detecting the modulation of P-glycoprotein in a solid tumor model by the reversal agent SDZ PSC 833.
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PMID:Characterization of P-glycoprotein transport and inhibition in vivo. 944 5

PSC 833, a nonimmunosuppressive cyclosporin, is able to inhibit the efflux of antitumor drugs mediated by P-glycoprotein (P-gp). The purpose of the present study is to compare the effect of PSC 833 on the tumor disposition of [3H]vincristine ([3H]VCR) and [3H]vinblastine ([3H]VBL) in in vitro and in vivo experiments from a pharmacokinetic point of view. In in vitro experiments, the effect of PSC 833 was investigated on the cellular uptake of [3H]VCR and [3H]VBL by HCT-15 and COLO 205, human colorectal tumor cell lines with extensive and minimal expression of P-gp, respectively. PSC 833 (2 microM) increased the cellular uptake of [3H]VCR and [3H]VBL by HCT-15 cells, but not that by COLO 205 cells, 8- and 6-fold, respectively, without affecting the initial influx rates. In addition, 2 microM PSC 833 reduced the efflux of [3H]VCR from HCT-15 cells to a level comparable with that from COLO 205 cells. Furthermore, the effect of PSC 833 on the tumor disposition of intravenously administered [3H]VCR and [3H]VBL was studied in tumor inoculated mice. Infusion of PSC 833 (10 microg/hr/mouse) increased the HCT-15 tumor disposition of [3H]VBL and [3H]VCR in vivo to a level comparable with that observed in vitro. These findings demonstrate that PSC 833 enhances the tumor disposition of vinca alkaloids by inhibition of P-gp-mediated efflux not only in vitro but also in vivo in a solid tumor model.
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PMID:Modulation of the tumor disposition of vinca alkaloids by PSC 833 in vitro and in vivo. 986 80

The present study examined the determinants of the penetration and accumulation of [(3)H]paclitaxel (12-12,000 nM) in three-dimensional histocultures of patient tumors and of a human xenograft tumor in mice. The results showed 1) significant and saturable drug accumulation in tumors, 2) extensive drug retention in tumors, and 3) a slower penetration but a more extensive accumulation in the xenograft tumor compared with patient tumors. Drug penetration was not rate-limited by drug diffusion from medium through the matrix supporting the histocultures. The difference in the expression of the mdr1 P-glycoprotein did not fully account for the difference in the drug accumulation in xenograft and patient tumors. Autoradiography and imaging were used to evaluate the spatial relationship between tumor architecture, tumor cell distribution, and drug distribution as a function of time and initial drug concentration in culture medium. The tumor cell density and the kinetics of drug-induced apoptosis were also evaluated. The results indicate that a high tumor cell density is a barrier to paclitaxel penetration and that the apoptotic effect of paclitaxel enhances its penetration in solid tumor. These factors are responsible for the time- and concentration-dependent drug penetration rate, with drug penetration confined to the periphery until apoptosis and reduction of epithelial cell density occurred at 24 h, after which time paclitaxel penetrated the inner parts of the tumor.
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PMID:Determinants of paclitaxel penetration and accumulation in human solid tumor. 1041 4

Pyrazoloacridine (PZA) is the first of a new class of rationally synthesized acridine derivatives to undergo clinical testing as an anticancer agent. Recent studies suggest that PZA might be a dual inhibitor of DNA topoisomerase I and DNA topoisomerase II that exerts its effects by diminishing the formation of topoisomerase-DNA adducts. Consistent with this unique mechanism of action, PZA exhibits broad spectrum antitumor activity in preclinical models in vivo. In addition, this agent displays several unique properties including solid tumor selectivity, activity against hypoxic cells, and cytotoxicity in noncycling cells. PZA also retains full activity against cells that are resistant to other agents on the basis of overexpression of P-glycoprotein or the multidrug resistance-associated protein (MRP). PZA has been studied in phase I trials in adults and children, and is currently undergoing broad phase II trials in a number of tumor types. No significant anti-tumor activity has been seen in gastrointestinal malignancies and prostate cancer. Results from ongoing or recently completed trials are awaited before the utility of this agent in our current armamentarium can be defined. Because of its unique properties, combination studies with other antineoplastic agents are warranted.
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PMID:Current status of pyrazoloacridine as an anticancer agent. 1055 21

Overexpression of P-glycoprotein (Pgp), a multidrug transporter encoded by the MDR1 gene, is associated with chemoresistance in some human solid tumor malignancies. To date, analyses of MDR1 levels in solid tumors have examined constitutive increases in expression at relapse. In the present study, we have evaluated the acute induction of MDR1 gene expression in a solid human tumor as a function of time in response to in vivo exposure to chemotherapy. Five patients with unresectable sarcoma pulmonary metastases underwent isolated single lung perfusion with doxorubicin. Relative MDR1 gene expression was measured in metastatic tumor nodules and normal lung specimens after initiation of chemoperfusion. In four of five patients, a 3-15-fold (median, 6.8) increase in MDR1 RNA levels was detected in tumors at 50 min after administration of doxorubicin. In contrast, normal lung samples had very low levels of MDR1 RNA prior to perfusion, and no acute increases were observed after therapy. These findings demonstrate, for the first time, that MDR1 gene expression can be rapidly activated in human tumors after transient in vivo exposure to cytotoxic chemotherapy.
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PMID:Rapid activation of MDR1 gene expression in human metastatic sarcoma after in vivo exposure to doxorubicin. 1058 42

Novel pyrimidinyl pyrazole derivatives were synthesized and examined for cytotoxic and antitumor activity. Mannich reaction was employed to construct this scaffold. Among the compounds synthesized, a series of propene derivatives exhibited a potent cytotoxic activity against some tumor cell lines including multidrug resistant cell lines due to the overexpression of P-glycoprotein. The vinyl bond moiety in the scaffold was believed to be required for the cytotoxic activity. Among them, compound 14 g, when administered intraperitoneally, showed potent antitumor activity against the malignant ascites caused by intraperitoneal inoculation of P388 cells in mice. This compound also showed high activity against a solid tumor Meth A mouse fibrosarcoma when administered both intraperitoneally and orally.
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PMID:Synthesis and antitumor activity of novel pyrimidinyl pyrazole derivatives. 1074 12

The saponin digitonin, the aglycone digitoxigenin and five cardiac glycosides were evaluated for cytotoxicity using primary cultures of tumor cells from patients and a human cell line panel (representing different cytotoxic drug-resistance patterns). Of these seven compounds, proscillaridin A was the most potent (IC(50): 6.4--76 nM), followed by digitoxin, and then ouabain, digoxin, lanatoside C, digitoxigenin and digitonin. Correlation analysis of the log IC(50) values for the cell lines in the panel showed that compound cytotoxicity was only slightly influenced by resistance mechanisms that involved P-glycoprotein, topoisomerase II, multidrug resistance-associated protein and glutathione-mediated drug resistance. Digitoxin and digoxin expressed selective toxicity against solid tumor cells from patients, while proscillaridin A expressed no selective toxicity against either solid or hematological tumor cells. The results revealed marked differences in cytotoxicity between the cardiac glycosides, both in potency and selectivity, and modes of action for cytotoxicity that differ from that of commonly used anticancer drugs.
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PMID:Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells. 1139 76

The existence of multidrug-resistant (MDR) cells in cancer is a major obstacle to effective cancer chemotherapy. Expression of P-glycoprotein (P-gp) in cancer cells causes resistance against paclitaxel and docetaxel, as well as against vincristine and doxorubicin (ADM). MS-209 is a novel MDR-reversal agent currently under clinical evaluation, which is shown to be active against ADM and vincristine resistance in MDR cancer cells in vitro and in vivo. In this paper, we report the combined effect of MS-209 with docetaxel in various MDR cancer cell lines that express P-gp. MS-209 at 3 microM effectively overcame docetaxel resistance in MDR cancer cells, and this concentration was achieved in blood plasma for > 7 h without serious toxicity. To study the effect of MS-209 in a clinically relevant model, we compared the antitumor efficacy of docetaxel alone with that of docetaxel combined with MS-209 at equitoxic doses in established solid tumor xenograft models. Treatment with docetaxel alone at the maximal tolerated dose (MTD) showed an apparent antitumor activity to an intrinsically resistant HCT-15 tumor xenograft, and MS-209 additionally potentiated the antitumor activity of docetaxel. Against a MCF-7/ADM tumor xenograft expressing larger amounts of P-gp, docetaxel alone at the MTD showed no antitumor activity, whereas the MTD of docetaxel combined with MS-209 greatly reduced MCF-7/ADM tumor growth. These results indicate that MS-209 could be a clinically useful drug to modulate MDR in docetaxel therapy.
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PMID:MS-209, a quinoline-type reversal agent, potentiates antitumor efficacy of docetaxel in multidrug-resistant solid tumor xenograft models. 1183 80

Arsenic trioxide (As(2)O(3)) has been found to induce apoptosis in leukemia cell lines and clinical remissions in patients with acute promyelocytic leukemia. In this study, we investigated the cytotoxic effect and mechanisms of action of As(2)O(3) in human tumor cell lines. As(2)O(3) caused inhibition of cell growth (IC(50) range, 3-14 microM) in a variety of human solid tumor cell lines, including four human non-small-cell lung cancer cell lines (H460, H322, H520, H661), two ovarian cancer cell lines (SK-OV-03, A2780), cervical cancer HeLa, and breast carcinoma MCF-7, as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry analysis showed that As(2)O(3) treatment resulted in a time-dependent accumulation of cells in the G(2)/M phase. We observed, using Wright-Giemsa and 4',6-diamidine-2-phenylindole-dihydrochloride staining, that As(2)O(3) blocked the cell cycle in mitosis. In vitro examination revealed that As(2)O(3) markedly promoted tubulin polymerization without affecting GTP binding to beta-tubulin. Immunocytochemical and EM studies of treated MCF-7 cells showed that As(2)O(3) treatment caused changes in the cellular microtubule network and formation of polymerized microtubules. Similar to most anti-tubulin agents, As(2)O(3) treatment induced up-regulation of the cyclin B1 levels and activation of p34(cdc2)/cyclinB1 kinase, as well as Bcl-2 phosphorylation. Furthermore, activation of caspase-3 and -7 and cleavage of poly(ADP-ribose) polymerase and beta-catenin occurred only in As(2)O(3)-induced mitotic cells, not in interphase cells, suggesting that As(2)O(3)-induced mitotic arrest may be a requirement for the activation of apoptotic pathways. In addition, As(2)O(3) exhibited similar inhibitory effects against parental MCF-7, P-glycoprotein-overexpressing MCF-7/doxorubicin cells, and multidrug resistance protein (MRP)-expressing MCF-7/etoposide cells (resistance indices, 2.3 and 1.9, respectively). Similarly, As(2)O(3) had similar inhibitory effect against parental ovarian carcinoma A2780 cells and tubulin mutation paclitaxel-resistant cell lines PTx10 and PTx22 (resistance indices, 0.86 and 0.93, respectively), suggesting that its effect on tubulin polymerization and G(2)/M phase arrest is distinct from that of paclitaxel. Taken together, our data demonstrate that As(2)O(3) has a paclitaxel-like effect, markedly promotes tubulin polymerization, arrests cell cycle at mitosis, and induces apoptosis. In addition, As(2)O(3) is a poor substrate for transport by P-glycoprotein and MRP, and non-cross-resistant with paclitaxel resistant cell lines due to tubulin mutation, suggesting that As(2)O(3) may be useful for treatment of human solid tumors, particularly in patients with paclitaxel resistance.
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PMID:Arsenic trioxide produces polymerization of microtubules and mitotic arrest before apoptosis in human tumor cell lines. 1218 29


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