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)

A drug-resistant human small cell lung cancer cell line, H209/V6, selected in the presence of increasing concentrations of 9-(4,6-O-ethylidene-beta-D-glucopyranosyl)-4'-demethylepipodophylloto xin (VP-16) from parental H209 cells, is 22-, 9-, and 4-fold resistant to VP-16, 4'-(9-acridinyl-amino)methanesulfon-m-anisidide, and doxorubicin, respectively, but not cross-resistant to 1,4-dihydroxy-5,8-bis((2-[(2-hydroxyethyl)amino] ethyl]-amino)-9,10-anthracenedione. These cells do not overexpress P-glycoprotein or the multidrug resistance-associated protein. Immunoblotting demonstrates that H209 cells contain the M(r) 170,000 isoform of topoisomerase II (topo II), while H209/V6 cells have a M(r) 160,000 enzyme but none of the M(r) 170,000 isoform. The cell lines have equal amounts of topo II beta. The H209/V6 cells have a 5-fold decrease in total immunoreactive topo II alpha. The catalytic and VP-16-induced DNA cleavage activities of the topo II present in 0.35 M NaCl nuclear extracts are decreased 2- to 3-fold in the drug-resistant cell line. This decrease in enzymatic activity is not consistent with either the 22-fold VP-16 resistance of the H209/V6 cell line or the approximately 5-fold decrease in immunoreactive topo II alpha in the cells. The M(r) 160,000 isoform from the H209/V6 cell line and the M(r) 170,000 enzyme from the parental cell line were purified so that the enzymatic activity of the 2 isoforms could be evaluated. The catalytic activities of the purified isoforms were found to be very similar. The drug-induced DNA cleavage activity of the M(r) 160,000 enzyme was reduced compared to the M(r) 170,000 enzyme. However, as with the nuclear extracts, the differences in enzymatic activity of the purified enzymes are considerably less than the level of drug resistance. Investigations of the subcellular localization of topo II by immunocytochemical techniques and cytoplasm/nuclear fractionation studies demonstrated that the M(r) 160,000 topo II alpha-related enzyme is primarily localized in the cytoplasm, while the M(r) 170,000 topo II alpha enzyme and topo II beta are located in the nucleus. These data imply that the deleted sequence in the M(r) 160,000 enzyme is not necessary for catalytic activity but is required to facilitate nuclear localization.
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PMID:Altered subcellular distribution of topoisomerase II alpha in a drug-resistant human small cell lung cancer cell line. 830 38

For investigation of relative differences in mRNA expression levels and of correlations in the expression of genes possibly involved in multidrug resistance (MDR) of acute myelogenous leukemias (AML), a complementary DNA polymerase chain reaction (cDNA-PCR) analysis was established for the genes encoding MDR1/P-glycoprotein, the multidrug resistance-associated protein (MRP), topoisomerase II alpha, topoisomerase II beta, topoisomerase I, glutathione S-transferase pi, protein kinase C (PKC) isozymes alpha, beta 1, beta 2, epsilon, eta, theta and cyclin A. In a first descriptive study comprising samples of childhood or adult AML we calculated the mean values from primary (n=14) or relapsed (n=23) states of the diseases, respectively. We found in the latter significant increases of MDR1, MRP, gst pi, and PKC theta gene expression. MDR1 and MRP gene expression levels were generally correlated (rs= +0.4128, P<0.02, n=37), as well as topoisomerase II alpha and cyclin A gene expression levels (rs= +0.8727, P<0.0001, n=35). Within the group of relapsed state AML a significant negative correlation between the gene expression levels of MDR1 and topoisomerase II alpha (rs= -0.5500, P<0.01, n=22) was observed. Remarkably, highly significant positive correlations were found for MDR1/PKC eta (rs= +0.5560, P<0.001, n=32), MRP/PKC theta (rs= +0.6573, P<0.0001, n=34) and MRP/PKC eta (rs= +0.5241, P<0.005, n=32).
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PMID:Expression of PKC isozyme and MDR-associated genes in primary and relapsed state AML. 864 57

The occurrence of multidrug resistance (MDR) is one of the main obstacles in the successful chemotherapeutic treatment of cancer. MDR cell lines are resistant to the so-called naturally occurring anti-cancer drugs, such as anthracyclines, Vinca alkaloids and epipodophyllotoxins, but are not cross-resistant to alkylating agents, antimetabolites and cisplatin. So far, three separate forms of MDR have been characterized in more detail: classical MDR, non-Pgp MDR and atypical MDR. Although all three MDR phenotypes have much in common with respect to cross-resistance patterns, the underlying mechanisms certainly differ. Atypical MDR is associated with quantitative and qualitative alterations in topoisomerase II alpha, a nuclear enzyme that actively participates in the lethal action of cytotoxic drugs. Atypical MDR cells do not overexpress P-glycoprotein, and are unaltered in their ability to accumulate drugs. In this review we will focus on classical and non-Pgp MDR. The molecular mechanism of classical and non-Pgp MDR is transcriptional activation of membrane-bound transport proteins. These transport proteins belong to the ATP-binding cassette (ABC) superfamily of transport systems. The classical MDR phenotype is characterized by a reduced ability to accumulate drugs, due to activity of an energy-dependent uni-directional, membrane-bound, drug-efflux pump with broad substrate specificity. The classical MDR drug pump is composed of a transmembrane glycoprotein (P-glyco-protein-Pgp) with a molecular weight of 170 kD, and is, in man, encoded by the so-called multidrug resistance (MDR1) gene. Typically, non-Pgp MDR has no P-gly-coprotein expression, yet has about the same cross-resistance pattern as classical MDR. This non-Pgp MDR phenotype is caused by overexpression of the multidrug resistance-associated protein (MRP) gene, which encodes a 190 kD membrane-bound glycoprotein (MRP). MRP probably works by direct extrusion of cytotoxic drugs from the cell and/or by mediating sequestration of the drugs into intracellular compartments, both leading to a reduction in effective intracellular drug concentrations. For the classical MDR phenotype, evidence is accumulating that it plays a role indeed, in clinical drug resistance, especially in some hematological malignancies (acute myeloid leukemia, multiple myeloma and non-Hodgkin's lymphoma) and solid tumors (soft tissue sarcomas and neuroblastoma). The association of MRP with clinical drug resistance has not been elaborated, yet, and studies on MRP expression in human cancer have just begun. We found that overexpression of MRP, as determined by RNase protection assay as well as by immunohistochemistry, occurs in several human cancers, among which are cancer of the lung, esophagus, breast and ovary, and leukemias. Further studies are indicated to establish whether elevated MRP expression at diagnosis is an unfavorable prognostic factor for clinical outcome of chemotherapy.
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PMID:Molecular mechanisms of multidrug resistance in cancer chemotherapy. 888 Aug 78

S16020-2 is a new olivacine derivative which has recently shown a marked antitumor activity in various experimental models. This study was undertaken in order to measure the inhibition of the proliferation of various sensitive and resistant tumor cell lines, by S16020-2, and to obtain information concerning its mechanism of action. For a continuous exposure, S16020-2 was as cytotoxic as adriamycin (ADR) (mean IC50 of about 28 nM) and on average, 46 fold more potent than elliptinium acetate (ELP), against a panel of 20 non-multidrug resistant cell lines. With a short exposure (1 hour) followed by a post-incubation of 95 hours in drug-free medium, S16020-2 was 5 and 6 fold more cytotoxic than ADR for human lung A549 and murine melanoma B16 cells, respectively. Furthermore, S16020-2 inhibited more actively the formation of colonies issued from proliferating cells, compared to colonies issued from quiescent A549 cells. Because quiescent cells demonstrated a 3 fold lower level of topoisomerase II alpha (topo II) than proliferating cells, these results suggest that this enzyme could be a potential target for S16020-2. In addition, as demonstrated by flow cytometric studies, S16020-2 intercalated into DNA and induced a cell cycle arrest in G2. Cell lines displaying the multidrug resistance (MDR) phenotype, P388/ADR-1, P388/ADR, P388/VCR-20, KB-A1, DC-3F/AD, S1/tMDR, and Colo320DM, were more sensitive to S16020-2 than to ADR or ELP, as shown by the mean resistance factors, 8, 201, and 23 respectively. In addition, the two cell lines displaying the pure classical MDR phenotype, linked exclusively to the P-glycoprotein (P-gp) overexpression (P388/VCR-20 and S1/tMDR), were as sensitive to S16020-2 as their sensitive parental counterparts, although they were resistant to ADR. S16020-2 is thus one of the most potent olivacine and ellipticine derivative yet characterized. The good cytotoxicity of S16020-2 against cells displaying a P-gp-mediated multidrug resistance, and its antitumor activity in vivo delineate an important chemotherapeutic potential for this drug.
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PMID:In vitro cytotoxicity of S16020-2, a new olivacine derivative. 891 38

The role of high-dose etoposide in the initial treatment of newly diagnosed adult ALL was assessed in a combined clinical and laboratory study. Therapy on protocol JH8802 consisted of two induction modules, module 1 containing prednisone, vincristine, high-dose etoposide and L-asparaginase (L-asp), followed by module 2 containing cytarabine (Ara-C) and daunorubicin (DNR). Patients achieving a complete remission (CR) underwent bone marrow transplantation (BMT) or intensive maintenance therapy. Results were compared to the preceding protocol (JH8302), which was similar except for omission of etoposide and L-asp. The CR rate following module 1 was 45% on protocol JH8802 and 9% on protocol JH8302 (p < 0.0002). Nonetheless, the two protocols had similar CR rates following module 2 (69% on protocol JH8302; 77% on JH8802) and indistinguishable survivals. Laboratory investigations performed on blasts harvested prior to chemotherapy revealed two factors that could potentially contribute to decreased etoposide sensitivity in ALL blasts. A flow microfluorimetry-based assay of nuclear DNR accumulation detected small P-glycoprotein (Pgp)-mediated decreases in drug accumulation in a quarter of the samples. Western blotting demonstrated that topoisomerase II was present in all samples but was diminished in amount compared to the Molt3 human ALL cell line. Immunoperoxidase staining with affinity-purified antibodies revealed that topo II alpha, the target for etoposide, was detectable in only a minority of the blasts (median 7.5%, range < 1-35%) at diagnosis. These observations raise the possibility that alterations in drug accumulation and diminished target enzyme levels might both limit the long-term efficacy of a single course of high dose etoposide administered early in the treatment of adult ALL.
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PMID:Addition of etoposide to initial therapy of adult acute lymphoblastic leukemia: a combined clinical and laboratory study. 902 88

Resistance of tumor cells to chemotherapeutic drugs can not only be caused by treatment with antineoplastic agents but also by radiotherapy. The aim of this study was to analyze whether ionizing radiation can influence the mRNA expression of proteins which have been found to be involved in drug resistance of tumor cells. Human tumor cell lines (MCF-7, LXF and Sk-Mel) were treated with single doses of irradiation (5, 10 and 20 Gy). The expression of the resistance related proteins glutathione S-transferase-pi (GST-pi), topoisomerase II alpha (Topo II), thymidylate synthase (TS), O6-methylguanine-DNA-methyltransferase (MGMT), P-glycoprotein (Pgp), glutathione peroxidase (GPX) multidrug resistance-associated protein (MRP) and also of the heat-shock protein 70 (HSP 70) were determined at the mRNA level during the time interval from 1.5 to 72 h post-irradiation and compared with their corresponding controls. We also examined whether a relationship exists between these proteins and the proliferative activity (histone 3, Ki-67, statin) of the cells. We found that exposure of MCF-7, LXF and Sk-Mel cells to ionizing radiation increases the expression of the mRNA of GST-pi. Topo II, TS, HSP 70 and proliferation markers were also altered by exposure to ionizing radiation, but there was no common response of the three cell lines. No significant changes were observed in the expression of MGMT, Pgp, GPX and MRP after radiation treatment. Drug resistance tests revealed that irradiated MCF 7 cells were less sensitive to doxorubicin than non-irradiated control cells. Our results indicate that ionizing irradiation modifies the expression of some proteins involved in drug resistance and the response of MCF 7 cells to doxorubicin and may, therefore, play a role in clinical drug response.
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PMID:Messenger RNA expression of resistance factors in human tumor cell lines after single exposure to radiation. 941 87

Previous studies have demonstrated decreased levels of DNA topoisomerase II alpha protein and messenger RNA in the Adriamycin-resistant P388 murine leukemia cell line P388/ADR/7 compared to the sensitive P388/4 cell line. An allelic fusion event involving the topoisomerase II alpha and the retinoic acid receptor a genes has been identified in these cells that probably contributes to the decreased topoisomerase II activity in P388/ADR/7 cells. However, this allelic mutation may be a minor contributor or even incidental to the resistance phenotype, since these cells display other candidate mechanisms of resistance, including increased P-glycoprotein, increased glutathione-S-transferase activity and an increased onset of DNA repair. To establish a role for topoisomerase II alpha in mediating the Adriamycin resistance phenotype, complementation of the mutant allele was attempted by transfecting the murine P388/ADR/7 cells with a human topoisomerase II alpha expression construct under the control of the human metallothionein IIA promoter. The majority of transfected cell lines that were obtained by selection in hygromycin B contained copies of the integrated expression construct that were rearranged. Only two of thirty-two transfected cell lines were found to contain a single, unrearranged copy of the human topoisomerase II alpha cDNA. P388/ADR/7 cell lines carrying an integrated, intact human topoisomerase II alpha expression vector were more sensitive to Adriamycin, daunorubicin, mitoxantrone, and etoposide, but not to actinomycin D and vincristine compared to control cells transfected with vector alone or cell lines with rearranged topoisomerase II alpha expression constructs. These findings suggest that topoisomerase II alpha is a selective and significant contributor to multifactorial resistance.
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PMID:Selective sensitization of adriamycin-resistant P388 murine leukemia cells to antineoplastic agents following transfection with human DNA topoisomerase II alpha. 949 16

Prostate cancer progresses from a localized disease to a widely disseminated malignancy. Each step along this progression pathway involves multiple genetic alterations that impart a survival advantage to the tumor cell over its normal counterparts and may confer resistance to therapy. Because metastatic prostate cancer is one of the most therapy-resistant human neoplasms, we studied the expression of certain molecular determinants of drug resistance in the context of tumor progression. Paraffin-embedded formalin-fixed resected prostates were chosen based on Gleason grade and surgical stage. Immunohistochemistry was used to detect the expression of multidrug resistance protein (MRP), topoisomerase II alpha, p53, glutathione S-transferase pi, Bcl-2, and P-glycoprotein in these specimens. We found that all of the proteins were expressed in resected prostate except for P-glycoprotein. The expression of MRP, topoisomerase II alpha, p53, and Bcl-2 increased with the Gleason grade. In addition, the expression of MRP, topoisomerase II alpha, and p53 increased with the surgical stage. In contrast, the glutathione S-transferase pi and Bcl-2 expression decreased with the increasing surgical stage. Stage was the strongest indicator of protein expression. These results suggest that drug resistance gene products are expressed in prostate cancer at the time of surgical resection. Thus, although the emergence of the "pan-resistance" phenotype in prostate cancer may partly be a function of the selection pressure exerted by therapeutic interventions, certain determinants of chemoresistance may be caused by genetic changes accompanying tumorigenesis.
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PMID:The expression of drug resistance gene products during the progression of human prostate cancer. 962 55

Malignant gliomas are largely resistant to current chemotherapeutic strategies often displaying a multidrug-resistant phenotype. Mechanisms involved in drug resistance are reduced cellular drug accumulation through membrane efflux pumps, drug detoxification as well as alterations in drug target specificity. In 27 primary and 17 secondary glioblastomas and their astrocytic precursor tumors, we studied the immunohistochemical expression profile of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), metallothionein, and topoisomerase II alpha. Glial tumor cells in all glioblastomas showed constant up-regulation of LRP, MRP, and topoisomerase II alpha. P-gp was found in 90% of the primary and 60% of the secondary glioblastomas. In precursor tumors, these drug resistance-related factors were expressed in varying proportions. Metallothionein, also found in normal and activated astrocytes, was retained in all neoplastic phenotypes. Furthermore, metallothionein, P-gp, LRP, and topoisomerase II alpha were strongly expressed by normal and neoplastic vessels which may confer to impaired penetration of therapeutic agents through the blood-brain and blood-tumor barrier. However, the expression profiles of drug resistance-related proteins neither differed between primary and secondary glioblastomas nor revealed any correlation to precursor or recurrent tumors. Nevertheless, inhibition of these factors may be promising approaches to the management of malignant gliomas.
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PMID:Drug resistance-associated factors in primary and secondary glioblastomas and their precursor tumors. 1126 2

Multidrug resistance-associated protein (MRP) is the major candidate molecule responsible for non-P-glycoprotein (PGp)-mediated multidrug resistance. We used a hammerhead anti-MRP ribozyme (alpha MRP-Rz) to inactivate MRP function in a multidrug resistant cancer cell line, KB8-5. The beta-actin promoter-driven alpha MRP-Rz sequence (pH beta/alpha MRP-Rz) was introduced into KB8-5 cells (KB8-5/alpha MRP-Rz) and we evaluated growth of the cell line. The gene expression of multidrug resistance-related molecules was estimated. Drug sensitivity was estimated by MTT assay in vitro. MRP mRNA expression was decreased in KB8-5/alpha MRP-Rz cells. The MTT assay showed increased IC50 values or resistance to doxorubicin (DOX), etoposide (VP-16) and cisplatin (CDDP) in KB8-5/alpha MRP-Rz cells. No significant differences were observed in expression of multidrug resistance gene (MDR1), thymidylate synthase, glutathione S-transferase pi or topoisomerase II alpha. The hammerhead ribozyme-mediated simple suppression of MRP mRNA expression was not sufficient to reverse multidrug resistance in the cancer cell line KB8-5.
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PMID:Modulation of multidrug resistance in a cancer cell line by anti-multidrug resistance-associated protein (MRP) ribozyme. 1139 79


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