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 efficacy of the calcium channel blocker verapamil for enhancing at low concentrations the cytotoxicity of unrelated antineoplastic drugs and for inhibiting at high concentrations cell proliferation has stimulated interest in the underlying mechanisms of these two diverse effects. We have selected two human brain tumor cell lines (a TE671 medulloblastoma and a A172 glioma line) for resistance against 100 uM verapamil to aid in the elucidation of the mechanism of verapamil's antiproliferative effect. Our first experiments on the selected TE671 medulloblastoma cells show that, in the presence of 100 uM verapamil, these cells grow at a rate similar to that observed for the sensitive cells in the absence of verapamil. This resistant clone continues to exhibit resistance toward verapamil for at least three days after the verapamil has been removed from the growth medium. In contrast to the sensitive cells, the resistant cells show only slight cell cycle phase alterations after removal of verapamil from the growth medium. This, together with an unchanged c-myc gene expression after removal of verapamil, indicates a stable phenotypic alteration that is responsible for the exhibited resistance toward the antiproliferative effects of the drug. Experiments designed to elucidate the mechanism of resistance showed that these cells are not cross-resistant to the antineoplastic drugs vincristine and adriamycin. Also, the resistance is not accompanied by increased amounts of the 170-180 kDa P-glycoprotein that has been implicated in resistance phenomena of cancer cells towards antineoplastic drugs.
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PMID:Human tumor cells resistant to verapamil. 274 89

The immunohistochemical detection of multidrug resistance (MDR1) gene products and their mRNA within brain tumor cells has already been described by Fojo et al. 1987. 63 specimens of astrocytomas and glioblastomas were analysed in the present study (Grading type 1 to 4) by means of the monoclonal antibody JSB1. The endothelial cells were positive only in astrocytic tumors with a grading of 1. Increasing tumor grading resulted in more positive immunological reactions in tumor cells. The most impressive reaction could be found in anaplastic astrocytoma and glioblastoma (G3 and G4). Overexpression of this P-glycoprotein, a plasma membrane component of a relative molecular mass of 170 kDa was not only found in tumor cells of anaplastic astrocytomas, but also in endothelial cells and some non-neoplastic brain diseases. Positive immunological reactions in protoplasmatic astrocytes could be demonstrated in cases of phenylketonuria (1/1), tuberculous leptomeningitis (2/2), SSPE (3/4), X-ray necrosis (1/1) and necrotizing viral encephalitis (1/4). According to this, it seems that astrocytes are able to express P-glycoprotein under the influence of some special metabolic conditions. This underlines the detoxicating function of reactive astrocytes within the total number of cells in the CNS.
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PMID:[Expression of P-glycoprotein as a multidrug resistance gene product in human reactive astrocytes and astrocytoma]. 794 20

A series of 7,8-dialkylpyrrolo[3,2-f]quinazolines were prepared as inhibitors of dihydrofolate reductase (DHFR). On the basis of an apparent inverse relationship between compound size and antifungal activity, the compounds were designed to be relatively small and compact. Inhibitor design was aided by GRID analysis of the three-dimensional structure of Candida albicans DHFR, which suggested that relatively small, branched alkyl groups at the 7- and 8-positions of the pyrroloquinazoline ring system would provide optimal interactions with a hydrophobic region of the protein. The compounds were potent inhibitors of fungal and human DHFR, with K(i) values as low as 7.1 and 0.1 pM, respectively, and were highly active against C. albicans and an array of tumor cell lines. In contrast to known lipophilic inhibitors of DHFR such as trimetrexate and piritrexim, members of this series of pyrroloquinazolines were not susceptible to P-glycoprotein-mediated multidrug resistance and also showed significant distribution into lung and brain tissue. The compounds were active in lung and brain tumor models and displayed in vivo activity against Pneumocystis carinii and C. albicans.
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PMID:High-affinity inhibitors of dihydrofolate reductase: antimicrobial and anticancer activities of 7,8-dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines with small molecular size. 863 13

The expression of human MDR1 P-glycoprotein (Pgp) in the capillary endothelial cells of the central nervous system has been demonstrated. The brain capillary endothelial cells maintain the structure and function of the blood-brain barrier. Recently, the human MDR1 Pgp (and its mouse homologue MDR1a Pgp) has been shown to function as an important part of this barrier, pumping out xenobiotics from endothelial cells into the lumen of capillaries resulting in the protection of the brain parenchyma. To examine whether the endothelial cells of the newly formed capillaries during neoangiogenesis within malignant human brain tumors express MDR1 Pgp, 35 adult surgical brain tumor specimens (29 gliomas and 6 tumors metastatic to the brain) were obtained from previously untreated patients and studied by a new immunohistochemical sandwich method developed in our laboratory using the JSB-1 monoclonal antibody. JSB-1 is specific for the Pgp product of the human MDR1 (and not MDR3) gene. This sensitive method allows the detection of Pgp in capillary endothelial cells of normal brain in conventional paraffin sections after formalin fixation. The endothelial cells of the newly formed capillaries in 25 of 29 gliomas (86%) and 3 of 6 metastatic tumors, immunostained positive for MDR1 Pgp. The tumor cells in 7 of 35 cases were also positive for Pgp. In the 35 brain tumor cases investigated, the endothelial cells were Pgp positive in the tumor-brain border and in the brain further from the tumor. Capillary endothelial cells of neovasculature in 137 malignant tumors (non-brain) obtained from previously untreated patients showed no MDR1 Pgp expression. These results demonstrated that MDR1 Pgp is expressed not only in the capillaries of normal brain but also in the majority of the newly formed capillaries of brain tumors. Multidrug resistance of brain tumors may result not only from the expression of resistance markers in neoplastic cells but also from the MDR1 Pgp expression in endothelial cells of tumor capillaries. Pgp in this special localization can exclude chemotherapeutic agents from tumor cells that are located around the capillaries. The therapeutic benefit and selectivity of chemotherapeutic agents in combination with a Pgp-reversing agent should be evaluated.
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PMID:MDR1 P-glycoprotein is expressed by endothelial cells of newly formed capillaries in human gliomas but is not expressed in the neovasculature of other primary tumors. 878 Mar 89

To elucidate the expression of the MDR1 gene products P-glycoprotein (Pgp) in endothelial cells of newly formed blood microvessels in brain tumors, 30 brain tumors were examined by immunohistochemistry using an anti-Pgp monoclonal antibody, JSB-1. Positive reactions for JSB-1 were detected in endothelial cells in newly formed microvessels in all 16 cases of glioma but not in the 4 meningiomas. Although endothelial cells in newly formed microvessels of all 10 metastatic carcinomas showed positive reactions, negative reactions were seen in those of the primary carcinomas. Compared with reactions of the endothelial cells of normal cerebral capillaries, weak reactions were found in the endothelial cells forming glomeruloid proliferation in newly formed microvessels in the eight glioblastomas and at the border of the surrounding cerebral tissue of the metastatic carcinomas. Since the endothelial cells showing glomeruloid proliferation also had a high proliferative cell nuclear antigen labeling index, the present findings demonstrate a negative relationship between positive reactions for Pgp and the proliferative activities of endothelial cells in cerebral capillaries.
Brain Tumor Pathol 1999
PMID:Expression of the multidrug-resistance P-glycoprotein (Pgp, MDR-1) by endothelial cells of the neovasculature in central nervous system tumors. 1053 20

Intracranial ependymomas are the third most common primary brain tumor in children. A variety of chemotherapy protocols have been introduced for the treatment of ependymoma although overall these have not contributed to patients outcome. To our knowledge, data on the prognostic value of immunoexpression of the chemoresistance-related proteins (ChRPs) in ependymomas are absent. Seventy-six patients with intracranial ependymomas who received combined treatment were studied retrospectively. Tumor specimens were immunohistochemically examined with antibodies to metallothioneins (MT), glutathione S-transferase pi (GST pi) and P-glycoprotein (P-GP). The results demonstrated significant preponderance of expression of all the above-mentioned ChRPs for the low-grade tumors. The progression-free survival time was found to be significantly shorter for immunonegative tumors in both tumor grades. Multivariate analysis using a Cox hazard model revealed that recurrence-free survival time is significantly associated with tumor grade, and MT and P-GP expression. Risk of recurrence increased for the high-grade ependymomas (hazard ratio 2.85; P = 0.004), and decreased for the MT-positive tumors (hazard ratio -2.72; P = 0.005) and for the P-GP-positive tumors (hazard ratio -2.02; P = 0.02). The obtained results allow one to conclude that ChRPs expression is closely associated with low-grade ependymomas and immunohistochemical findings may be estimated as a predictor for local tumor progression.
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PMID:Prognostic value of immunoexpression of the chemoresistance-related proteins in ependymomas: an analysis of 76 cases. 1084 92

Multidrug resistance (MDR) is associated with the expression of P-glycoprotein (P-gp), an ATP-dependent transporter which expels anti-cancer drugs from cells. In the present study, MDR1 P-gp was immunodetected by Western blot analysis in 60 human brain tumors, including meningiomas, schwannomas, low-grade gliomas (astrocytomas, pilocytic astrocytomas) and high-grade gliomas (anaplastic astrocytomas, glioblastomas and anaplastic oligodendrogliomas). Most samples from primary tumors expressed P-gp at the same levels as normal brain tissue except for schwannomas, in which levels were reduced by 65%, and meningiomas, in which levels were more than 10-fold higher in 7 of 10 samples. P-gp levels were 70% and 95% lower in brain metastases from melanomas and lung adenocarcinomas, respectively, than in normal brain tissue. These results indicate that the majority of primary brain tumors express MDR1 P-gp and that its high expression levels in meningiomas may be a marker for this type of brain tumor.
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PMID:Expression of multidrug-resistance P-glycoprotein (MDR1) in human brain tumors. 1139 22

Paclitaxel (Taxol), a cytotoxic natural product that disrupts microtubule integrity, is being clinically evaluated for use against gliomas. We examined paclitaxel-induced killing in seven cell lines derived from human malignant astrocytic gliomas and medulloblastomas with the goal of characterizing range of sensitivity, contribution of P-glycoprotein 170-mediated drug efflux to resistance, and cross-resistance with alkylating agents. Exposure to paclitaxel for 8 h or less produced biphasic survival curves for all lines, with 40-75% of cells comprising a subpopulation that was 9-26 times more resistant to paclitaxel than the more sensitive fraction. Increasing exposure to 24 h eliminated the resistant subpopulation, increasing sensitivity 50- to 400-fold. The dose producing one log of kill (LD10) after a 24-h exposure ranged from 4 to 18 nM, comparable to concentrations in the cerebrospinal fluid of brain tumor patients given a 3-h infusion of paclitaxel. Concurrent exposure to paclitaxel and either nimodipine or verapamil, inhibitors of P-glycoprotein activity, did not increase sensitivity, demonstrating that the fivefold range in sensitivity was not due to P-glycoprotein-mediated drug efflux. Importantly, there was no correlation between LD10 for paclitaxel and LD10 for 1,3-bis(2-chloroethyl)-1-nitrosourea, streptozotocin, and temozolomide, indicating no expression of cross-resistance to these different classes of tumoricidal agents. Our results suggest that greater clinical efficacy of paclitaxel against malignant brain tumors may be obtained by infusion for 24 h or longer and support the use of paclitaxel in combination with alkylating agents.
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PMID:Characterization of paclitaxel (Taxol) sensitivity in human glioma- and medulloblastoma-derived cell lines. 1155 Mar 5

The poor prognosis of glioma patients is partly based on the minor success obtained from chemotherapeutic treatments. Resistance mechanisms at the tumor cell level may be, in addition to the blood-brain barrier, involved in the intrinsic chemo-insensitivity of brain tumors. We investigated the expression of the drug-transporter proteins P-glycoprotein (P-gp) and multidrug-resistance protein 1 (MRP1) in cell lines (N = 24) and primary cell cultures (N = 36) from neuroectodermal tumors, as well as in brain tumor extracts (N = 18) and normal human astrocytes (N = 1). We found that a considerable expression of P-gp was relatively rare in glioma cells, in contrast to MRP1, which was constitutively overexpressed in cells derived from astrocytomas as well as glioblastomas. Also, normal astrocytes cultured in vitro expressed high amounts of MRPI but no detectable P-gp. Meningioma cells frequently co-expressed P-gp and MRP1, while, most of the neuroblastoma cell lines express higher P-gp but lower MRP1 levels as compared to the other tumor types. Both, a drug-exporting and a chemoprotective function of P-gp as well as MRP1 could be demonstrated in selected tumor cells by a significant upregulation of cellular 3H-daunomycin accumulation and daunomycin cytotoxicity via administration of transporter antagonists. Summing up, our data suggest that P-gp contributes to cellular resistance merely in a small subgroup of gliomas, but frequently in neuroblastomas and meningiomas. In contrast, MRP1 is demonstrated to play a constitutive role in the intrinsic chemoresistance of gliomas and their normal cell counterpart.
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PMID:Expression and functional activity of the ABC-transporter proteins P-glycoprotein and multidrug-resistance protein 1 in human brain tumor cells and astrocytes. 1212 64

The expression of P-glycoprotein was investigated immunohistochemically in 26 brain tumor tissues and compared with the findings of technetium-99m methoxyisobutylisonitrile single photon emission computed tomography (99mTc-MIBI SPECT) to clarify the effect of P-glycoprotein on the diagnostic accuracy. P-glycoprotein labeling index of both tumor cells and vascular endothelial cells showed no clear relationship with the findings of 99mTc-MIBI SPECT imaging. Expression of P-glycoprotein has no effect on the diagnostic accuracy of 99mTc-MIBI SPECT.
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PMID:Effect of expression of P-glycoprotein on technetium-99m methoxyisobutylisonitrile single photon emission computed tomography of brain tumors. 1220 84


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