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:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug resistance often results in failure of anticancer chemotherapy in leukemias. Several mechanisms of drug resistance are known with multidrug resistance (MDR) being the best characterized one. MDR can be due to enhanced expression of certain genes (MDR1, MRP or LRP), alterations in glutathione-S-transferase activity or GSH levels and to reduction of the amount or the activity of topoisomerase II. Here we review the current status of the clinical significance of the various mechanisms of MDR in leukemias and also discuss possibilities for the reversal of MDR. MDR1 gene expression has been seen in many leukemias, notably in acute myeloid leukemia (AML) and blast crisis of chronic myeloid leukemia. Both MDR1 RNA and P-glycoprotein expression of the leukemic cells have been shown to correlate with poor clinical outcome in AML. However, preliminary results indicate that the MRP gene as well as the LRP gene can be expressed in AML. Thus, drug resistance in leukemias appears to be multifactorial. P-glycoprotein-mediated MDR can be reversed by several drugs. These resistance modifiers are currently evaluated with regard to their clinical efficacy. Despite some encouraging results, reversal of drug resistance and subsequent improvement in clinical outcome remains to be shown.
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PMID:Multidrug resistance in leukemias and its reversal. 903 Oct 75

An experimental model of advanced human neuroblastoma, IGR-N-91, which is able to disseminate in the nude mouse, has been described. The present study was designed to ascertain which cell population from the IGR-N-91 primary tumour actually disseminates throughout the animals. In s.c. IGR-N-91 tumour xenografts, 3 areas, called pearly, vascularized and haemorrhagic, depending on the presence of blood vessels and haemorrhagic suffusions, were consistently observed and independently resected. Molecular analysis of tumour materials revealed a significant increase in MYCN and max gene transcript levels in the haemorrhagic area, as compared with the pearly and vascularized areas. Given the growth kinetics observed both in vitro and in vivo, and the DNA flow-cytometry profiles of tumour cells obtained from the haemorrhagic area, this transcriptional increase did not appear to be associated with enhanced proliferation. In this area of the tumours, multidrug-resistance-related genes, i.e., MDRI, MRP, GST-pi and topoisomerase II alpha were activated concomitantly with MYCN and max genes. The same observations were made, except for the topoisomerase-II alpha gene, when sub-lines derived from metastases were compared with that derived from the primary tumour. These data demonstrate that over-expression of several genes determining the multi-drug-resistance phenotype precedes the metastatic spread of IGR-N-91 NB tumour cells in the nude mouse. Data also suggest that the cell sub-population exhibiting this pleiotropic over-expression within the primary tumour undergoes selection during metastatic dissemination.
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PMID:Pleiotropic over-expression of multidrug-resistance-related genes is correlated to MYCN and max mRNA accumulation during tumour progression in the IGR-N-91 human neuroblastoma model. 903 51

Drug-resistance in cell lines and in malignant human tumours is associated with dysregulation of several genes including mdr1, MRP1, GST-pi, bcl-2, DNA topoisomerase II alpha and beta, and thymidine kinase I. mRNA expression was evaluated by quantitative RT-PCR coupled with HPLC in three human tumour cell lines and drug-resistant (DR)-sublines. DR sublines from RPMI-8226 and KB cells specifically overexpressed the mdr1 gene without major changes observed in other putative DR-associated genes. In contrast, the DR-H69 cells exhibited a 34-fold overexpression of the MRP gene accompanied by significant down-regulation of both DNA topoisomerase II alpha and bcl-2 mRNA gene expression, by factors of 43 and 13 respectively. These results demonstrate the concomitant down regulation of topoisomerase II alpha and bcl-2 genes in response to DR. Furthermore, differential patterns of gene dysregulations appear to vary depending upon both the drug used to select resistance and cellular origin.
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PMID:Assessment of drug-induced dysregulations among seven resistance-associated genes in human tumour cell lines. 904 17

The acquisition of drug-resistant tumour cells is the main problem in the medical treatment of a range of malignant diseases. In recent years, three new classes of anti-cancer agents, each with a novel mechanism of action, have been brought forward to clinical trials. These are the topoisomerase I (topo I) poisons topotecan and irinotecan, which are both camptothecin derivatives, the taxane tubulin stabilizers taxol and taxotere and, finally, the antimetabolite gemcitabin, which is active in solid tumours. The process of optimizing their use in a combination with established agents is very complex, with numerous possible drug and schedule regimens. We describe here how a broad panel of drug-resistant small-cell lung cancer (SCLC) cell lines can be used as a model of tumour heterogeneity to aid in the selection of non-cross-resistant regimens. We have selected low-fold (3-10x) drug-resistant sublines from a classic (NCI-H69) and a variant (OC-NYH) SCLC cell line. The resistant cell lines include two sublines with different phenotypes towards alkylating agents (H69/BCNU and NYH/CIS), two sublines with different phenotypes against topo I poisons (NYH/CAM and NYH/TPT) and three multidrug resistant (MDR) sublines (H69/DAU, NYH/VM, and H69/VP) with combinations of mdr1 and MRP overexpression as well as topoisomerase II (topo II) down-regulation or mutation. Sensitivity to 20 established and new agents was measured in a standardized clonogenic assay. Resistance was highly drug specific. Thus, none of the cell lines was resistant to all drugs. In fact, all resistant cell lines exhibited patterns of collateral sensitivity to various different classes of drugs. The most intriguing pattern was collateral sensitivity to gemcitabin in two cell lines and to ara-C in five drug-resistant cell lines, i.e. in all lines except the lines resistant to topo I poisons. Next, all sensitivity patterns in the nine cell lines were compared by correlation analysis. A high correlation coefficient (CC) for a given pair of compounds indicates a similar pattern in response in the set of cell lines. Such data corroborate the view that there is cross-resistance among the drugs. A numerically low coefficient indicates that the two drugs are acting in different ways, suggesting a lack of cross-resistance between the drugs, and a negative correlation coefficient implies that two drugs exhibit collateral sensitivity. The most negative CCs (%) to the new drug leads were: taxotere-carmustine (BCNU) (-75), taxol-cisplatin (-58), ara-C-taxol (-25), gemcitabin-doxorubicin (-32), camptotecin-VM26 (-41) and topotecan-VP16 (-17). The most negative correlations to the clinically important agent VP-16 were: cisplatin (-70); BCNU (-68); camptothecin (-38); bleomycin (-33), gemcitabin (-32); ara-C (-21); topotecan (-17); melphalan (-3); and to the other main drug in SCLC treatment cisplatin were: doxorubicin (-70); VP-16 (-70); VM-26 (-69); mAMSA (-64); taxotere (-58); taxol (-58). Taxol and taxotere were highly correlated (cross-resistant) to VP-16 (0.76 and 0.81 respectively) and inversely correlated to cisplatin (both -0.58). Similarly, camptothecin and topotecan were correlated to cisplatin but inversely correlated to VP-16 and other topo II poisons. From the sensitivity data, we conclude that collateral sensitivity and lack of cross-resistance favours a cisplatin-taxane or topo I-topo II poison combination, whereas patterns of cross-resistance suggest that epipodophyllotoxin-taxane or topo I poison-cisplatin combinations may be disadvantageous.
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PMID:In vitro cross-resistance and collateral sensitivity in seven resistant small-cell lung cancer cell lines: preclinical identification of suitable drug partners to taxotere, taxol, topotecan and gemcitabin. 906 9

Chemotherapeutic drug resistance is a major clinical problem and cause for failure in the therapy of human cancer. One of the goals of molecular oncology is to identify the underlying mechanisms, with the hope that more effective therapies can be developed. Several mechanisms have been suggested to contribute to chemoresistance: 1) amplification or overexpression of the P-glycoprotein family of membrane transporters (eg, MDR1, MRP, LRP) which decrease the intracellular accumulation of chemotherapy; 2) changes in cellular proteins involved in detoxification (eg, glutathione S-transferase pi, metallothioneins, human MutT homologue, bleomycin hydrolase, dihydrofolate reductase) or activation of the chemotherapeutic drugs (DT-diaphorase, nicotinamide adenine dinucleotide phosphate:cytochrome P-450 reductase); 3) changes in molecules involved in DNA repair (eg, O6-methylguanine-DNA methyltransferase, DNA topoisomerase II, hMLH1, p21WAF1/CIP1; 4) activation of oncogenes such as Her-2/neu, bcl-2, bcl-XL, c-myc, ras, c-jun, c-fos, MDM2, p210 BCR-abl, or mutant p53. An overview of these resistance mechanisms is presented, with a particular focus on the role of oncogenes. Some current strategies attempting to reverse their effects are discussed.
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PMID:Role of oncogenes in resistance and killing by cancer therapeutic agents. 909 Apr 98

The purpose of the present study was to evaluate whether intermittent exposure to a constant dose of doxorubicin selects for multidrug resistance (MDR) in RPMI 8226 human myeloma cells and, if so, to determine the molecular mechanism. In an attempt to approximate clinical doxorubicin treatment in vitro, cells were exposed to a fixed dose of doxorubicin for 4 d alternating with growth in drug-free medium for 17 d. An MDR subline emerged, termed 8226/DOXint5, which was 3-4-fold resistant to doxorubicin, etoposide and m-AMSA, and 1.6-fold resistant to vincristine. Sensitivity to docetaxel, melphalan and cisplatin was normal. Verapamil normalized vincristine sensitivity but had little effect on resistance to the other agents. Cellular uptake and retention of daunorubicin and vincristine were reduced by approximately 10%. The 8226/DOXint5 cells showed diminished DNA topoisomerase IIalpha expression and increased expression of the multidrug resistance protein MRP. Expression of MDR1/P-glycoprotein was not detected. Immunostaining showed 70% of the cells to over-express the lung-resistance protein LRP. This new MDR myeloma cell line may prove to be a useful model for the development of strategies to overcome low-level, multifactorial MDR, which might be a common phenomenon in clinical myeloma treated with doxorubicin.
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PMID:Intermittent exposure to doxorubicin in vitro selects for multifactorial non-P-glycoprotein-associated multidrug resistance in RPMI 8226 human myeloma cells. 913 43

Illudins are novel low molecular weight natural products cytotoxic to human tumor cells in vitro. Illudin-derived analogs are effective against experimental human cancers nonresponsive to conventional anticancer agents. It is not known why some illudin analogs are more efficacious in vitro and in vivo than other analogs. Therefore, the in vitro cytotoxicity of the parent compound illudin S towards tumor cells was characterized using radiolabeled drug. Two cell lines sensitive at nanomolar concentrations using only a 15-min exposure period displayed a saturable, energy-dependent accumulation of illudins with relatively low K(m) and high Vmax values. A nonsensitive cell line, requiring millimolar concentrations to achieve in vitro toxicity, showed minimal illudin uptake with higher K(m) and lower Vmax values. No release of radioactivity could be demonstrated from tumor cells, indicating that there was no efflux of illudin S (or metabolites) from these cells. The number of intracellular illudin S molecules required to kill 50% of cells of different tumor cell lines varied from 78000 to 1114000 molecules per cell and was correlated with the 2-h IC50 value determined using a colony-forming assay. Illudin S was cytotoxic to a variety of multidrug-resistant tumor cell lines regardless of whether resistance was mediated by gp170/mdrl, gp180/MRP, GSHTR-pi, topoisomerase I, topoisomerase II, increased DNA repair capacity, or alterations in intracellular thiol content. Information obtained in this study could be used to design clinical phase I trials and to develop analogs with improved therapeutic indexes.
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PMID:Characterization of cellular accumulation and toxicity of illudin S in sensitive and nonsensitive tumor cells. 913 32

The heterogeneous nature of an adriamycin-selected human MDR squamous lung cell line, DLKP-A, was investigated by isolating and characterising 9 of its clonal subpopulations. The DLKP-A cell line exhibits resistance to the classical MDR drugs, overexpresses P-glycoprotein and displays reduced topoisomerase II amounts. The clonal cell lines exhibit a wide range of resistance extents, with the most resistant clone displaying 9 times the extent of adriamycin resistance observed in the least resistant clone. A number of clones exhibit sensitivity to the concentration of adriamycin in which the parental cell line was selected, possibly indicating cooperation between the more and less resistant cells. Detailed analysis of 4 of the clonal subpopulations revealed broadly similar drug resistance mechanisms. Alterations in expression of the MDR-associated genes MDR1 and Topo IIalpha were observed, with no detectable changes in the expression of MDR3, MRP, GSTpi, Topo IIbeta, Topo I and CYP1A1 noted. However, each clonal cell line displayed a distinct extent of expression of MDR1 and Topo IIalpha and further characterisation of the clones indicated that other modes of drug resistance may exist in at least one of the cell lines. In particular, 2 of the clones (DLKPA6B and DLKPA11B) which have almost identical drug resistance profiles appear to have quite different mechanisms of resistance. The clonal subpopulations possess individual growth rates, amounts of adriamycin accumulation and susceptibility to toxicity-enhancement by MDR-modulating agents. It was possible to generate a cell line with a drug toxicity profile similar to DLKP-A by mixing some of the clonal subpopulations. Our results provide evidence of heterogeneity within an MDR human cell population with respect to resistance and expression of MDR-associated genes.
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PMID:Isolation from a human MDR lung cell line of multiple clonal subpopulations which exhibit significantly different drug resistance. 918 Jan 64

Variants of the human ovarian carcinoma cell line, OAW42, exhibiting low-level intrinsic resistance (OAW42-SR) and drug-induced higher-level resistance (OAW42-A1 & OAW42-A), were studied along with a sensitive clonal population (OAW42-S) which was isolated from OAW42-SR. Expression of the MDR-associated protein P-170, the more recently discovered LRP (lung resistance-related protein) and MRP (multidrug resistance-associated protein), topoisomerase II alpha and beta, GST pi and the cytoskeletal proteins, cytokeratin 8 and vimentin, were studied (using immunocytochemistry and Western blotting techniques) in conjunction with drug (doxorubicin) accumulation and subcellular distribution. Expression of mRNA for P-170, MRP, topoisomerase 11 alpha and beta and GST pi was studied using RT-PCR (reverse transcriptase polymerase chain reaction). Results indicate differential co-expression of four MDR-associated parameters (P-170, MRP, LRP and reduced topoisomerase II alpha and beta) in the OAW42-SR and OAW42-A1 variants, whereas resistance in the OAW42-A variant appeared to be mainly P-170 mediated. Comparable amounts of MRP and greater amounts of LRP were detected in the OAW42-S cells compared to the OAW42-SR variant (which showed increased resistance compared to the OAW42-S cells), but all cell lines expressed similar low-level amounts of MRP mRNA (by RT-PCR). GST pi levels did not differ markedly between variants. Increased levels of the cytoskeletal proteins were observed with increasing levels of resistance. The relative resistance of the variants, OAW42-SR and OAW42-A1, compared with OAW42-S was seen to change during increased serial passaging of the cells. There was greater drug accumulation by the sensitive OAW42-S cell line compared with that of the resistant variants, particularly the most highly resistant OAW42-A cells. Both verapamil and cyclosporin A effectively restored the accumulation defects seen in the resistant variants, cyclosporin A being the more effective of the two. Sub-cellular location of drug was predominantly in the nucleus with maximum levels seen in the sensitive OAW42-S variant and minimum levels in the most resistant OAW42-A clone.
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PMID:Co-expression of MDR-associated markers, including P-170, MRP and LRP and cytoskeletal proteins, in three resistant variants of the human ovarian carcinoma cell line, OAW42. 927 50

The efficacy of all chemotherapeutic agents is limited by the occurrence of drug resistance. To further understand resistance to topoisomerase (topo) II inhibitors, 50 sublines were isolated as single clones from parental cells by exposure to etoposide or m-AMSA. Subsequently, a population of cells from each sublines was exposed to three-fold higher drug concentrations allowing 16 stable sublines to be established at higher extracellular drug concentration. Quantitative aspects of MRP and C-MOAT were studied by Northern blotting in 66 resistant cell lines. Increased MRP mRNA was observed in 48.5% of resistant cell lines (64.7% of etoposide resistant cells and 31.3% of m-AMSA resistant cell lines). Increased C-MOAT mRNA was also observed in 39.4% of resistant cell lines (41.2% in etoposide resistant cell lines and 37.5% in m-AMSA resistant cell lines). To characterize the function of C-MOAT, cellular accumulation assay for 3H-etoposide was performed in three resistant cell lines which overexpress C-MOAT but do not express MRP. Accumulation of etoposide was reduced in the cell lines. Our findings suggest that increased MRP and O-MOAT mRNA seems to be an important mechanism of resistance to topo II inhibitors.
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PMID:[Expression of ATP binding cassette superfamily (multidrug resistance-1, multidrug resistance-associated protein, human canalicular multispecific organ anion transporter) mRNA in etoposide and m-AMSA resistant cell lines]. 935 Feb 40


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