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)

In view of the poor response of ependymomas to chemotherapy, it may be hypothesized that these tumors have intrinsic drug resistance to some chemotherapeutic agents. The expression of drug resistance may be specific to a single agent or may involve multiple drugs. Among several mechanisms of drug resistance, P-glycoprotein (Pgp) has been the subject of considerable attention in clinical practice. In order to assess the possible participation of Pgp in the chemotherapeutic resistance of ependymomas, 42 biopsy specimens from 35 patients with ependymoma seen at our institutions were studied by immunohistochemistry with two monoclonal antibodies: C219 (Signet) and UIC-2 (Dr. Roninson's gift). In addition, four cases were studied by polymerase chain reaction after reverse transcription to detect transcripts of Pgp. Our results showed that in 35 samples there was a positive reaction for Pgp with both antibodies; two biopsy samples were positive only with C219 and three others with UIC-2; the remaining two samples were negative with both antibodies. Of the four cases studied by RT-PCR, three showed MDR1 transcripts. These results support our hypothesis of Pgp-mediated intrinsic multidrug resistance in these tumors.
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PMID:Ependymomas in children express the multidrug resistance gene: immunohistochemical and molecular biologic study. 902 53

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

Ependymomas, rare neoplasms of the central nervous system, occur predominantly in children. They are highly vascularized, and histological findings show many perivascular rosettes of tumoral cells radially organized around capillaries. Treatment of ependymomas relies on surgery combined with radio- or chemotherapy, but the efficiency of chemotherapy is limited, probably because of their multidrug resistance (MDR) phenotype. Progress in the therapy of these neoplasms is dramatically limited by the absence of cell line models. We established conditions for the long-term culture of human tumoral ependymocytes and their 3D coculture in Matrigel with endothelial cells. Histological, immunological, and ultrastructural studies showed that the morphological features (microvilli, cilia, and caveolae) of these cultured cells were similar to those of the tumor in vivo. The cells expressed potential oncological markers related to the immature state of tumoral cells (nestin and Notch-1), their tumorigenicity [caveolae and epidermal growth factor-receptor (EGF-R)], or the MDR phenotype [P-glycoprotein (P-gp)]. The expression of P-gp, EGF-R, and caveolin-1 by these tumoral ependymocytes could be useful in studies on new drugs. This coculture model might represent a new powerful tool to study new therapeutic delivery strategies in tumoral cells.
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PMID:Establishment of human tumoral ependymal cell lines and coculture with tubular-like human endothelial cells. 1223 16

Tamoxifen, a non-steroidal anti-estrogen widely used against breast cancer, is also useful for treatment of other malignancies, due to its sensitizing effect on other chemotherapeutic agents and radiation. We have investigated the advantages of combining tamoxifen with one of the commonly used cancer chemotherapeutic drug, etoposide (VP-16) in brain tumor cell lines. While tamoxifen (10 microM) increased etoposide cytotoxicity 8.3-fold in the human glioma cell line (HTB-14), it increased etoposide cytotoxicity 47.5- and 40-fold in two primary cell lines established from pediatric medulloblastoma patients (MCH-BT-31 and MCH-BT-39), respectively. Similarly, in the pediatric ependymoma cell lines (MCH-BT-30 and MCH-BT-52), tamoxifen enhanced etoposide cytotoxicity 6- and 2.68-fold, respectively. CalcuSyn analysis of cytotoxicity data showed that tamoxifen and etoposide combinations were synergistic with combination index values ranging from 0.243 to 0.369 at IC50 level among different pediatric brain tumor cell lines. Tamoxifen is also cytotoxic at higher concentrations (> 20 microM) in brain tumor cells. To understand the mechanism underlying the tamoxifen modulation of etoposide cytotoxicity, we analyzed expression of P-glycoprotein (P-gp), insulin-like growth factor-I receptor (IGF-IR), IGF-I, IGF-II and estrogen receptor as well as protein kinase C (PKC) activity. While P-gp, IGF-IR and IGF-I were not affected, enhanced inhibition of PKC, and IGF-II were observed in brain tumor cells treated with tamoxifen and etoposide combination as compared to cells treated with either drug alone. Tamoxifen at 10 microM when combined with etoposide at 0-100 microM concentrations reduced PKC activity 77% compared to only 58% without tamoxifen. IGF-II expression decreased to 48.6% of the untreated control in the combination treatment as compared to 31.2% for etoposide alone and 26.2% for tamoxifen alone treatments. These results suggest that inhibitory effect of tamoxifen on brain tumor cells manifest through different mechanisms involving inhibition of targets such as PKC and IGF-II.
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PMID:Tamoxifen modulation of etoposide cytotoxicity involves inhibition of protein kinase C activity and insulin-like growth factor II expression in brain tumor cells. 1507 44

The management of ependymomas remains one of the most frustrating issues in pediatric neuro-oncology. Gross total resection is not always possible, and intensive chemotherapy and craniospinal radiotherapy have made no clear advances. Moreover, the chemoresistance of ependymomas may be explained by the expression of membrane transport molecule P-glycoprotein (P-gp). In this study the expression of cyclooxygenase 2 (COX-2) and the role of the specific COX-2 inhibitor NS-398 in growth and multi-drug resistance of ependymomas were investigated. COX-2 protein expression was assessed in 19 ependymomas immunohistochemically, and the effect of NS-398 on growth and multi-drug resistance was investigated using two primary cultured ependymoma cell lines. COX-2 protein expression was observed in 15 (79%) of the 19 ependymomas. NS-398 was found to reduce the proliferation of monolayer cell cultures in a dose- and time-dependent manner and to induce apoptosis and lower bcl-2 protein levels. After NS-398 treatment, Western blotting showed reduced P-gp expression and a rhodamine 123 efflux assay demonstrated a significant decrease in P-gp activity. Our findings demonstrate that COX-2 is overexpressed in ependymomas and that NS-398 is able to induce apoptosis and suppress P-gp expression and activity.
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PMID:Overexpression of cyclooxygenase-2 in childhood ependymomas: role of COX-2 inhibitor in growth and multi-drug resistance in vitro. 1525 9

Ependymomas are neuroepithelial tumors that arise from the ependymal layer bordering the cerebral ventricles and spinal canal. Intracranial ependymoma represents a major encephalic tumor in children, while spinal ependymoma develops more frequently in adults. To understand the pharmacoresistance that characterizes this tumoral entity, we analyzed the level of expression and localization of three major efflux transport proteins with a multidrug resistance function, P-glycoprotein, multidrug resistance-related protein 1 (MRP1) and breast cancer resistance protein (BCRP), in a series of 25 ependymomas from both children and adults. Real-time-PCR analysis showed that all three genes were expressed in all tumors, with no apparent correlation between the level of expression and either age or tumor grade. The MRP1 transcript was expressed at a significantly higher level in spinal tumors than in intracranial tumors. The expression of the proteins corresponding to these genes was confirmed by Western blot analysis. In an immunohistochemical study, P-glycoprotein and BCRP were shown to be associated with the tumoral vessels, where they presented a luminal localization, a prerequisite for their efflux drug activity into the blood. These data indicate that a biochemical, transporter-dependent blood-tumor barrier may exist in ependymomas, which may reduce the tumoral bioavailability of lipophilic and amphiphilic anticancer drugs.
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PMID:P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) localize in the microvessels forming the blood-tumor barrier in ependymomas. 2040 35