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)

Selection protocols were designed to determine whether non-cytotoxic chemomodifiers can influence the evolution of the drug-resistant phenotype. To this end, the human multiple myeloma cell line RPMI 8226 (8226/S) was selected with either doxorubicin, verapamil or doxorubicin plus verapamil. Using this approach low-level multi-drug-resistant (MDR) cell lines were obtained when 8226/S was selected with doxorubicin only or doxorubicin plus verapamil but not with verapamil only. The MDR phenotypes obtained were mechanistically distinct. In doxorubicin only-selected cells (8226/dox4), drug resistance was mediated by over-expression of the MDR1 gene and its cognate protein P-glycoprotein. In contrast, the drug resistance seen in the doxorubicin plus verapamil-selected cells was mediated through decreases in topoisomerase II protein levels and catalytic activity and not by P-glycoprotein over-expression. Cells selected with verapamil alone did not become resistant to any of the drugs tested. None of the 3 selected cell lines showed any changes in MRP gene expression when compared with 8226/S. Our results indicate that the inclusion of verapamil during drug selection with doxorubicin influences the drug-resistant phenotype by preventing the selection of MDR1/P-glycoprotein-positive cells.
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PMID:Verapamil suppresses the emergence of P-glycoprotein-mediated multi-drug resistance. 863 68

Gene expression was analyzed by cDNA-PCR at the mRNA level in bone marrow samples (>80% blasts) from ALL (28 primary, 22 first relapses, 10 recurrent relapses), from AML (14 primary, 23 relapses), In peripheral blood lymphocytes from CLL (five untreated, 10 treated), in one CML in blast crisis in the course of the disease (four samples), and in bone marrow samples from healthy donors (12 specimens). We found low mean MDR1 expression in primary ALL, first relapses of ALL, and primary AML. Significantly higher mean relative MDR1 expression levels were seen in recurrent relapses of ALL, and in the group of relapsed state AML. MDR1 expression measured intermediate in bone marrow samples from healthy donors. The CLL lymphocytes showed generally relatively high MDR1 expression levels. MRP gene expression measured very similar in primary ALL, first relapses of ALL, primary AML, and normal bone marrow. Significantly increased MRP mRNA levels were observed in the groups of recurrent ALL and relapsed state AML. CLL lymphocytes also showed high MRP expression levels. A combined increase of MDRI (about 20-fold) and MRP (about four-fold) was monitored in samples obtained from the CML in blast crisis after chemotherapy. While no significant differences of the mean topoisomerase IIbeta mRNA levels were found throughout, a significantly decreased topoisomerase IIalpha gene expression was measured in first and recurrent relapses of ALL. In CLL lymphocytes either the expression of the topoisomerase IIalpha gene was not detectable by cDNA-PCR, or it measured very low. Topoisomerase IIalpha gene expression was correlated to cyclin A gene expression in the samples of acute leukemias, Indicating the link of topoisomerase IIalpha expression to the proliferative activity of these leukemic blast cells. Our results point to a potentially multifactorial emergence of multidrug resistance in particular states and types of leukemias.
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PMID:MDR1, MRP, topoisomerase IIalpha/beta, and cyclin A gene expression in acute and chronic leukemias. 865 99

Inhibitors of calcium-calmodulin-dependent processes, 1-[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-piperazine KN-62 and trifluoperazine (TFP), at non-cytotoxic concentrations (2 and 5 microM, respectively) enhanced etoposide (VP-16) cytotoxicity in Adriamycin-resistant (HL-60/ADR0.05) cells (3- to > 50-fold). In contrast to TFP, the inhibitor KN-62 was able to reverse resistance in HL-60/ADR0.05 cells at VP-16 concentrations that produced equivalent cytotoxicity in sensitive (HL-60/S) cells. Unlike TFP, the cellular accumulation of VP-16 in the presence of KN-62 was enhanced 1.5- to 2-fold in HL-60/S (MDR1 -ve) and HL-60/ADR0.05 (MDR1 +ve) cells. To achieve equivalent cytotoxicity, levels of VP-16 in the resistant cells were > 4-fold lower in the presence of KN-62 compared with treatment with VP-16 alone. The sensitizing effects of both KN-62 and TFP were due to enhancement (2- to 4-fold) of VP-16-induced topoisomerase II (TOPO II)-mediated DNA cleavable complex formation, and depletion of the 170 kDa (alpha) TOPO II isoform. The DNA damage induced by VP-16 in the presence of KN-62 or TFP resulted in the rapid induction of apoptosis and depletion of cells in "S" phase of the cell cycle. Both 5 microM TFP and 2 microM KN-62 enhanced the phosphorylation of 170 kDa TOPO II 1.6-fold and 1.5-fold, respectively. Results suggest that the inhibitory effect of KN-62 or TFP on calcium-calmodulin-dependent processes may be mechanistically involved in sensitizing resistant cells to VP-16 by enhancing TOPO II-mediated DNA damage.
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PMID:Cellular events involved in the sensitization of etoposide-resistant cells by inhibitors of calcium-calmodulin-dependent processes. Role for effects on apoptosis, DNA cleavable complex, and phosphorylation. 895 49

Human colon tumor xenografts are known to be refractory to most chemotherapeutic anticancer drugs. Recent studies have demonstrated that a class of topoisomerase I inhibitors, camptothecins, exhibits unprecedented antitumor activity against human colon tumor xenografts in nude mice (Giovanella et al., 1989; Potmesil et al., 1991). The ability of camptothecin to overcome MDR1-mediated resistance may be one important contributing factor to camptothecin's impressive activity (Chen et al., 1991). If this interpretation is correct, it will be promising to develop new drugs that can overcome MDR1-mediated resistance for treating certain human solid tumors. Admittedly, MDR1-mediated resistance is only one of the many mechanisms of drug resistance in tumor cells. Designing new drugs for various resistance tumors will require fundamental information on various drug resistance mechanisms. It will eventually be possible to tailor drugs for particular drug-resistant tumors. Using topoisomerase inhibitors, we have begun to understand some of the parameters that may have to be considered for rational drug design.
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PMID:Design of topoisomerase inhibitors to overcome MDR1-mediated drug resistance. 899 11

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

Recent studies have suggested that 3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (beta-lapachone) inhibits DNA topoisomerase I by a mechanism distinct from that of camptothecin. To study the mechanism of action of beta-lapachone, a series of beta-lapachone and related naphthoquinones were synthesized, and their activity against drug-sensitive and -resistant cell lines and purified human DNA topoisomerases as evaluated. Consistent with the previous report, beta-lapachone does not induce topoisomerase I-mediated DNA breaks. However, beta-lapachone and related naphthoquinones, like menadione, induce protein-linked DNA breaks in the presence of purified human DNA topoisomerase IIalpha. Poisoning of topoisomerase IIalpha by beta-lapachone and related naphthoquinones is independent of ATP and involves the formation of reversible cleavable complexes. The structural similarity between menadione, a para-quinone, and beta-lapachone, an ortho-quinone, together with their similar activity in poisoning topoisomerase IIalpha, suggests a common mechanism of action involving chemical reactivity of these quinones. Indeed, both quinones form adducts with mercaptoethanol, and beta-lapachone is 10-fold more reactive. There is an apparent correlation between the rates of the adduct formation with thiols and of the topoisomerase II-poisoning activity of the aforementioned quinones. In preliminary studies, beta-lapachone and related naphthoquinones are found to be cytotoxic against a panel of drug-sensitive and drug-resistant tumor cell lines, including MDR1-overexpressing cell lines, camptothecin-resistant cell lines, and the atypical multidrug-resistant CEM/V-1 cell line.
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PMID:Induction of DNA topoisomerase II-mediated DNA cleavage by beta-lapachone and related naphthoquinones. 904 37

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

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

Decreased topoisomerase II (Topo II) activity results in resistance to antineoplastic agents targeting this enzyme. Dox1V derived from human multiple myeloma RPMI 8226 demonstrated a 4-fold resistance to doxorubicin in the absence of MDR1 overexpression or topo II mutations (Futscher B.W., Foley N., Gleason-Guzman M., Meltzer P.S., Sullivan D.M., and Dalton W.S., Int'l. J. Cancer, 66: 520-5, 1996.). Consistent with its drug resistant phenotype, a 2- to 3-fold decrease in topo II expression was identified. To investigate the molecular basis for decreased topo II expression in Dox1V, a semi-quantitative analysis of Topo II activity, protein level and mRNA transcript were performed. The results demonstrated that reduced Topo II activity is due to a decreased mRNA level. Southern blot and sequencing experiments revealed wild-type sequence of the topo II promoter in the drug resistant cells. Transient gene expression assays demonstrated that topo II is transcriptionally down-regulated in Dox1V independent of the promoter sequence of the endogenous alleles. Instead, the activity of a ubiquitous transcription factor CP-1 (NF-Y) interacting with the topo II promoter is decreased. The decrease in CP-1/NF-Y activity in Dox1V is correlated well with the decrease in topo II transcriptional activity, transcript level, Topo II protein and enzyme activity. Therefore, transcriptional down-regulation resulted from a reduced CP-1/NF-Y activity is responsible for decreased topo II expression in Dox1V cells.
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PMID:Decreased CP-1 (NF-Y) activity results in transcriptional down-regulation of topoisomerase IIalpha in a doxorubicin-resistant variant of human multiple myeloma RPMI 8226. 926 89


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