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)

N-Benzyladriamycin-14-valerate (AD 198)-resistant murine J774.2 macrophage-like cells (A300) exhibited a novel mechanism of resistance in which P-glycoprotein was overexpressed without decreased AD 198 accumulation. Cross-resistance to Adriamycin (ADR), N-benzyladriamycin, and Adriamycin-14-valerate was due, at least in part, to reduced accumulation, suggesting that circumvention of P-glycoprotein-mediated transport was associated with extreme lipophilicity conferred by both substitutions. Thus, unlike multidrug resistance mediated by either P-glycoprotein, the multidrug resistance-associated protein (MRP), or decreased topoisomerase II activity, cross-resistance in A300 cells was highly structure-specific. In order to further characterize the specificity of AD 198 resistance, the cytotoxicity, accumulation, and intracellular localization of a series of 3'-morpholinyl, 3'-deamino and halogenated ADR congeners that have been reported to circumvent MDR was determined in AD 198-resistant J774.2 and P388 AD 198-resistant cells. Cross-resistance correlating with increased AD 198 resistance was observed for 2'-bromo-4'-epi-hydroxy-daunomycin (13-fold), morpholinyl doxorubicin (24-fold), and 4'-iodo-4'-deoxydoxorubicin (2.8-fold), but was attributable to decreased accumulation. Cross-resistance to 3'-hydroxy-14-O-palmitoyl-doxorubicin (6-fold) was not due to reduced accumulation. No cross-resistance was observed for the highly cytotoxic metabolite of WP474, 3'-hydroxyldoxorubicin (hydroxyrubicin; WP159), nor for the much less cytotoxic 3'-O-benzylated congeners, including 3'-O-benzyl-doxorubicin-14-valerate. These findings indicate that AD 198 resistance confers cross-resistance to compounds that, like AD 198, localize in the cytoplasm but are metabolized to highly cytotoxic, nuclear-localizing compounds.
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PMID:N-benzyladriamycin-14-valerate (AD 198)-resistant cells exhibit highly selective cross-resistance to other anthracyclines that circumvent multidrug resistance. 790 37

Two Chinese hamster ovary cell clones resistant to okadaic acid (OA) were isolated. The OA-resistance was associated with resistance to colchicine, Vinca alkaloids and inhibitors of DNA topoisomerase (topo) II. Drug accumulation assays showed that the intracellular levels of OA, vinblastine and vincristine, but not the topo II inhibitor etoposide, were significantly lowered in the OA-resistant mutants than in the parental cells. These results, together with the finding of an increased level of P-glycoprotein (P-gp) in the mutant cells, indicate that the resistances to OA, Vinca alkaloids and colchicine are due to a P-gp-mediated mechanism. Resistance to topo II inhibitors, however, was associated with reduced activity of topo II. Thus, at least two events, overexpression of P-gp and reduction of topo II activity, occurred in a single OA-resistant cell line, contributing to expression of the MDR phenotype.
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PMID:Chinese hamster ovary cells resistant to okadaic acid express a multidrug resistant phenotype. 791 70

Although the DNA topoisomerases are critical intracellular targets of a number of clinically important anticancer drugs, the mechanism(s) by which inhibition of these enzymes causes cell death are poorly understood. We found that treatment of human leukemic lymphoblasts (CCRF-CEM) with teniposide (VM-26), under conditions that stabilize DNA-topoisomerase II complexes, caused the formation of internucleosomal DNA ladders. However, it appeared unlikely that the VM-26-stabilized DNA-topoisomerase II-cleavable complexes directly produce these internucleosomal DNA ladders, since similar nucleosomal DNA ladders were observed following either continuous or a short (1 h) exposure of cells to VM-26. Under continuous exposure to VM-26, the internucleosomal DNA ladders were associated with the transient induction of c-jun mRNA in a dose-dependent fashion, reaching maximum expression at 6 h after treatment with VM-26 and being down-regulated to basal levels by 12 h. The induction of c-jun mRNA by VM-26 apparently preceded DNA ladder formation. However, in CEM sublines selected for resistance to VM-26 (CEM/VM-1 and CEM/VM-1-5; approximately 50- and 140-fold resistant, respectively) and which display the phenotype of multidrug resistance associated with altered DNA topoisomerase II (at-MDR), we found that the induction of c-jun mRNA by VM-26 and subsequent DNA ladder formation were progressively attenuated in proportion to the resistance of the cells, apparently due in part to decreased stabilization of DNA-topoisomerase II-cleavable complexes. Further, the attenuated induction of c-jun in the at-MDR cells was found to be associated with a decreased rate of c-jun transcription and an increase in the instability of its mRNA following VM-26 treatment. The attenuation of c-jun mRNA induction was also reflected in decreased production of c-Jun protein in the at-MDR cells. Of interest was the fact that no significant induction of c-fos mRNA by VM-26 was observed in either CEM or at-MDR cells. Furthermore, the induction of c-jun was related to the activation of AP-1 DNA-binding activity in a time- and dose-dependent manner in CEM cells, whereas the activation of AP-1 binding was attenuated in at-MDR cells in proportion to their resistance to VM-26. Using Jun and Fos family member antibody inhibition experiments in gel-mobility shift assays, we found that AP-1-binding activity appeared to be preferentially mediated by c-Jun/Fra-1 heterodimers in both CEM and at-MDR cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differences between drug-sensitive and -resistant human leukemic CEM cells in c-jun expression, AP-1 DNA-binding activity, and formation of Jun/Fos family dimers, and their association with internucleosomal DNA ladders after treatment with VM-26. 806 63

In order to clarify the mechanism of drug resistance in human myeloma cells, we investigated the expressions of DNA topoisomerase I and topoisomerase II gene and the genes possibly related to drug resistance; multi-drug resistant gene 1 (MDR-1), glutathione S-transferase class pi gene (GST-pi), by Northern blotting. Myeloma cells in eight of 15 cases prior to chemotherapy expressed topoisomerase I mRNA considerably, while the expression of topoisomerase II mRNA was detected weakly in only one of 16 myeloma patients. There was not any correlation between expression of topoisomerase I mRNA and clinical drug resistance. Significant expression of MDR-1 mRNA and P-glycoprotein was not detected in 25 cases of multiple myeloma prior to chemotherapy and even after several courses of VAD (vincristine, adriamycin and dexamethasone) therapy by Northern blotting and immunostaining using monoclonal anti-P-glycoprotein antibody (MRK-16), respectively. On the other hand, 16 of 21 myeloma cases showed significant expression of GST-pi protein and GST-pi mRNA with the various strengths, but there was no apparent correlation between GST-pi mRNA expression and clinical response. Therefore these data suggest that expression of the genes we tested may not determine the level of drug resistance in multiple myeloma, but lower or no significant expression of topoisomerase II mRNA in most myeloma cells indicates the possibility that topoisomerase II inhibitors such as VP-16 and topoisomerase II-mediated cytotoxic drugs such as adriamycin, are not so effective for the treatment of multiple myeloma.
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PMID:Expressions of DNA topoisomerase I and II gene and the genes possibly related to drug resistance in human myeloma cells. 809 26

KB-A1 and KB-A10 are 2 multi-drug-resistant cell lines which are 100- and 1,000-fold resistant to Adriamycin, respectively. We have examined the expression of P-glycoprotein at the molecular and cellular levels in these human carcinoma cells. Both MDR cell lines, when compared to the parental KB-3-1, show characteristic increases in mdr 1 gene copy number, an increase in mdr 1 mRNA expression, a corresponding increase in transcription rate and a consequent over-expression of P-glycoprotein. However, the more highly resistant KB-A10 cells have a lower gene copy number, express less mdr 1 mRNA and contain less P-glycoprotein than the A1 cell line. To determine whether higher levels of cellular resistance were attributable to enhanced efficacy of P-glycoprotein or to other cellular regulatory mechanisms, we examined other major cellular properties known to be associated with the mdr phenotype. Both the KB-A1 and KB-A10 lines exhibit similar increases in protein kinase C activity as compared to the drug-sensitive parent. In addition, neither glutathione-S-transferase nor topoisomerase II activities account for enhanced resistance of the KB-A10 cells. The above observations are contrary to the premise that the level of drug resistance is necessarily proportional to expression of P-glycoprotein or to other common factors thought to participate in drug insensitivity; consequently, new mechanisms of resistance must be in operation in these cells.
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PMID:Anomalous expression of P-glycoprotein in highly drug-resistant human KB cells. 809 16

We have examined the effects of a group of DNA topoisomerase II (topo II) inhibitors, merbarone, aclarubicin, SN22995, RP60475F, and fostriecin, in CCRF-CEM cells and two sublines, CEM/VM-1 and CEM/VM-1-5, that were selected for increasing resistance to teniposide (VM-26). The teniposide-resistant sublines have been termed "at-MDR" for altered topo II-associated multidrug resistance. These topo II inhibitors differ from the "classic" inhibitors such as teniposide in that they do not stabilize DNA-topo II complexes. In this study, we found that our at-MDR cell lines express little or no cross-resistance to these "non-classic" topo II inhibitors. Merbarone and SN22995 inhibited VM-26-mediated DNA-topo II complexes in CEM cells only when they were added before VM-26. Since they did not deplete topo II protein, it suggested that these drugs may inhibit topo II activity before the enzyme binds to DNA, thereby preventing stabilization of VM-26-mediated topo II-DNA complexes. Continuous exposure of CEM cells to merbarone, SN22995, or VM-26 caused G2 arrest, as determined by flow cytometry. Likewise, at-MDR cells continuously treated with VM-26 also arrested in G2. By contrast, treatment of at-MDR cells with either merbarone or SN22995 produced a qualitatively different pattern; the at-MDR cells first accumulated in G2 but then escaped the G2 block and proceeded into mitosis with elongated and intertwined chromosomes but failed to divide. Their DNA was re-replicated, however, and the cells eventually accumulated at the 8N DNA stage. Given that both wild-type and mutant topo II alpha alleles are expressed in the at-MDR cells (B. Y. Bugg, M. K. Danks, W. T. Beck, and D. P. Suttle. Expression of a mutant DNA topoisomerase II in CCRF-CEM human leukemic cells selected for resistance to teniposide. Proc. Natl. Acad. Sci. USA, 88: 7654-7658, 1991), we hypothesize that drugs such as merbarone may inhibit the activity of wild-type topo II alpha, allowing the aberrant activity of the mutant enzyme to be revealed during chromosome condensation and sister chromatid segregation.
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PMID:Teniposide-resistant CEM cells, which express mutant DNA topoisomerase II alpha, when treated with non-complex-stabilizing inhibitors of the enzyme, display no cross-resistance and reveal aberrant functions of the mutant enzyme. 826 8

We have studied the genetic alterations acquired during selection of a cloned human leukaemic cell line (CEM/VP-1) that is 15-fold more resistant to the anticancer topoisomerase II-inhibitor etoposide than parental CCRF-CEM cells. CEM/VP-1 cells exhibit an 'atypical MDR' phenotype: cross resistance to other topo II inhibitors (but not Vinca alkaloids) and expression of a drug-resistant topo II activity. Cytogenetic and molecular studies revealed that the cell line carried multiple genetic changes affecting TOP2 genes encoding both topo II alpha and beta isoforms. CEM/VP-1 was diploid, 47,XX,+20, and appears to have been preferentially selected from a 1% diploid subpopulation present in the tetraploid parental cells. The same chromosomal abnormalities were present in resistant and sensitive cells except for an acquired 3p- change most likely deleting one TOP2 beta allele. PCR/DNA sequence analysis and allele-specific hybridisation showed that one of two TOP2 alpha alleles expressed in CEM/VP-1 cells had acquired a Lys-797-->Asn codon change. This mutation lies close to the catalytic Tyr-804 residue of the protein and may interfere with drug-induced trapping of the cleavable complex. Alternatively, it could exert a loss of function phenotype. CEM/VP-1 cells did not exhibit codon 449 or 486 TOP2 alpha mutations in the ATP binding domain reported in two other resistant cell lines. Diploid selection and multiple changes observed in CEM/VP-1 cells appear to be consequences of the recessive phenotype of at-MDR. These results may be useful in approaching the mechanisms of clinical resistance.
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PMID:Novel selection and genetic characterisation of an etoposide-resistant human leukaemic CCRF-CEM cell line. 838 8

We investigated four mechanisms of intrinsic chemoresistance in a series of 67 human brain tumours including 31 gliomas (one grade I ganglioglioma, nine grade II and 10 grade III astrocytomas, 11 glioblastomas), 13 cerebral metastases, one medulloblastoma, one malignant teratoma, three ependymomas and 18 meningiomas. We studied four genes by northern blotting: multidrug-resistance (MDR 1), glutathione-s transferase (GST pi), dihydrofolate reductase (DHFR), and topoisomerase II (Topo II). The Topo II gene was absent in the normal adult brain (100%) and in 64% of the tumour samples tested. A second gene, GST pi, was found to be overexpressed in 38% of brain tumours. The two other chemoresistance-related genes were occasionally overexpressed in brain tumours (2% for MDR1, 9% for DHFR). Our results provide evidence that chemoresistance is intrinsic to the brain tissue and seems likely to be a multifactorial process.
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PMID:A study of the expression of four chemoresistance-related genes in human primary and metastatic brain tumours. 838 72

In contrast to the classic anthracyclines (doxorubicin and daunorubicin), aclarubicin (ACLA) does not stimulate topoisomerase II (topo II) mediated DNA-cleavage. This distinction may be important with respect to topo II-related drug resistance, and the aim of this study was to clarify drug-structures responsible for this difference. Various ACLA analogs were tested for: (a) interaction with purified topo II, (b) induction of DNA cleavage in cells, (c) cellular uptake and (d) cytotoxicity. A remarkable distinction was seen between analogs containing the chromophore aklavinone (AKV) (e.g. ACLA) which have a carboxymethyl group (COOCH3) at C-10 and drugs with a beta-rhodomycinone (RMN) chromophore with hydroxyl groups at C-10 and at C-11. Thus, RMN-containing analogs, including the aglycone RMN itself, effectively stimulated topo II-mediated DNA cleavage. In contrast, AKV-containing drugs inhibited DNA cleavage and antagonized cytotoxicity mediated by RMN-containing drugs. In OC-NYH/VM cells, exhibiting multidrug resistance due to an altered topo II phenotype (at-MDR), cross-resistance was only seen to the RMN-containing drugs whereas no cross-resistance was seen to the non-DNA cleaving AKV-containing compounds. Thus, our data show that one domain in the anthracycline is of particular importance for the interaction with topo II, namely the positions C-10 and C-11 in the chromophore, and further that at-MDR was circumvented by a COOCH3 substitution at position C-10. These findings may provide guidance for the synthesis and development of new analogs with activity in at-MDR cells.
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PMID:Different modes of anthracycline interaction with topoisomerase II. Separate structures critical for DNA-cleavage, and for overcoming topoisomerase II-related drug resistance. 839 Feb 59

A human bladder cancer cell line resistant to adriamycin (ADM), T24/ADM9 has been established in vitro by exposing T24 parent cells to progressively higher concentrations of the drug over a period of 12 months. The T24/ADM9 cells were found to be 9 times more resistant to ADM than the T24 parent, and showed various degrees of cross-resistance to an ADM derivative, vinea alkaloids and a DNA topoisomerase II (Topo II)-targeting agent, etoposide. No significant differences was observed in the cellular accumulation of ADM between the T24/ADM9 and T24 parent cells. A Northern blot analysis showed an overexpression of multidrug resistance-associated protein (MRP) mRNA, but no overexpression of multidrug resistance-1 (MDR1) mRNA was observed in the T24/ADM9 cells. A flow cytometric analysis showed that the MDR1 gene product, P-glycoprotein (Pgp), is not expressed on the T24/ADM9 cells. T24/ADM9 showed approximately the parental level of DNA Topo II catalytic activity. In Western blot and Northern blot analyses, however, the cellular level of DNA topo II was apparently much lower in T24/ADM9 than in the T24 parent. Thus, these results suggest that a decreased cellular level of DNA Topo II and an overexpression of MRP gene may be responsible for the expression of an MDR phenotype in the T24/ADM9 cells and that such non-Pgp-mediated, atypical MDR may develop in bladder cancer treated with chemotherapy including ADM.
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PMID:Non-P-glycoprotein-mediated atypical multidrug resistance in a human bladder cancer cell line. 856 4


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