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)

Recombinant human tumor necrosis factor (rHuTNF) is a cytokine, with some antitumor activity, released by stimulated monocytes-macrophages. In vivo and in vitro cytotoxicity studies testing the effectiveness of rHuTNF alone or in combination with chemotherapeutic agents have been carried out. We have evaluated the direct cytotoxic effect of rHuTNF on a human epithelial ovarian cancer cell line in vitro (A2774), alone or in combination with Etoposide (VP16) or Doxorubicin (Doxo), some topoisomerase II (Topo II) targeted drugs, or in combination with Cisplatin (CDDP), a not Topo II interactive drug. Our results suggest that rHuTNF is directly cytotoxic and that it is also able to induce a potentiation of VP16- or Doxo-cytotoxicity, but it is unable to potentiate CDDP-cytotoxicity. These data represent a reasonable basis for combining rHuTNF with Topo II inhibitors within phase I studies. The combination regimen could be tested in ovarian cancer patients.
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PMID:Synergistic cytotoxic effects of recombinant human tumor necrosis factor and Etoposide (VP16) or Doxorubicin on A2774 human epithelial ovarian cancer cell line. 1157 50

Anthranoid laxatives, belonging to the anthraquinones as do anthracyclines, possibly increase colorectal cancer risk. Anthracyclines interfere with topoisomerase II, intercalate DNA and are substrates for P-glycoprotein and multidrug resistance-associated protein 1. P-glycoprotein and multidrug resistance-associated protein 1 protect colonic epithelial cells against xenobiotics. The aim of this study was to analyse the interference of anthranoids with these natural defence mechanisms and the direct cytotoxicity of anthranoids in cancer cell lines expressing these mechanisms in varying combinations. A cytotoxicity profile of rhein, aloe emodin and danthron was established in related cell lines exhibiting different levels of topoisomerases, multidrug resistance-associated protein 1 and P-glycoprotein. Interaction of rhein with multidrug resistance-associated protein 1 was studied by carboxy fluorescein efflux and direct cytotoxicity by apoptosis induction. Rhein was less cytotoxic in the multidrug resistance-associated protein 1 overexpressing GLC4/ADR cell line compared to GLC4. Multidrug resistance-associated protein 1 inhibition with MK571 increased rhein cytotoxicity. Carboxy fluorescein efflux was blocked by rhein. No P-glycoprotein dependent rhein efflux was observed, nor was topoisomerase II responsible for reduced toxicity. Rhein induced apoptosis but did not intercalate DNA. Aloe emodin and danthron were no substrates for MDR mechanisms. Rhein is a substrate for multidrug resistance-associated protein 1 and induces apoptosis. It could therefore render the colonic epithelium sensitive to cytotoxic agents, apart from being toxic in itself.
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PMID:Cytotoxicity of rhein, the active metabolite of sennoside laxatives, is reduced by multidrug resistance-associated protein 1. 1198 86

Recently, accumulated statistical data indicate the protective effect of caffeine consumption against several types of cancer diseases. There are also reports about protective effect of caffeine and other xanthines against tumors induced by polycyclic aromatic hydrocarbons. One of the explanations is based on biological activation of such carcinogens by cytochromes that are also known for metabolism of caffeine. However, there is also numerous data indicating reverse effect on cytotoxicity of anticancer drugs that inhibit the action of topoisomerase I (e.g. Camptothecin or Topotecan) and topoisomerase II inhibitors (e.g. Doxorubicin, Mitoxantrone or mAMSA). In this work we tested the hypothesis that the caffeine protective effect is the result of sequestering of aromatic mutagens by formation of stacking (pi-pi) complexes. As the models for the study we have chosen two well-known mutagens, that do not require metabolical activation: quinacrine mustard(QM, aromatic, heterocyclic nitrogen mustard) and mechlorethamine (NM2, aliphatic nitrogen mustard). The flow cytometry study of these agents' action on the cell cycle of HL-60 cells indicated that caffeine prevents the cytotoxic action of QM, but not that of NM2. The formations of stacking complexes of QM with caffeine were confirmed by light absorption, calorimetric measurements and by molecular modeling calculation. Using the statistical thermodynamics calculations we calculated the "neighborhood" association constant (K(AC)=59+/-2M(-1)) and enthalpy change (DeltaH(0')=-116cal mol(-1)); the favorable entropy change of complex formation (DeltaS(0')=7.72cal mol(-1)K(-1), due to release of several water molecules, associated with components in the process of complex formation). The Gibbs' free energy change of QM-CAF formation is DeltaG(0')=-2.41kcal mol(-1). We were unable to detect any interaction between NM2 and caffeine either by spectroscopic or calorimetric measurement. In order to establish, whether the intercalation of QM plays any role in cytotoxic effect we tested, as a control, non-alkylatiatig, but also intercalating QM derivative-quinacrine (Q). The later had no cytostatic effect on HL-60 cell even at there order of higher concentration than QM or NM2 but, similar to QM forms (which we demonstrated) stacking complexes with caffeine (K(AC)=75+/-3M(-1)). These results strongly indicate, that the attenuating effect of caffeine on cytotoxic or mutagenic effects of some mutagens, is not the results of metabolic processes in the cells, but simply the physicochemical process of sequestering of aromatic molecules (potential carcinogens or mutagens) by formation of stacking complexes with them. The caffeine may then act as the "interceptor" of potential carcinogens (especially in the upper part of digesting track where its concentration can reach the concentration of mM level). There is, however, no indication either in the literature or in our experiments that xanthines can reverse the damage to nucleic acids when the damage to DNA has already occurred.
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PMID:The modulation of the DNA-damaging effect of polycyclic aromatic agents by xanthines. Part I. Reduction of cytostatic effects of quinacrine mustard by caffeine. 1199 30

Idarubicin (IDA) is an anthracycline used during treatment of acute myelogenous leukaemia (AML) and is clinically important because of its potency and lipophilicity (compared to the related compounds daunorubicin and doxorubicin). These drugs target DNA topoisomerase II (topo II), a nuclear enzyme that regulates DNA topology. Topo II poisoning leads to the trapping of an intermediate in the enzyme's cycle termed the "cleavable complex." This study aims to increase understanding of drug interactions by use of the "TARDIS" (trapped in agarose DNA immunostaining) assay to measure drug-induced topo II cleavable complexes in individual cells treated with anthracyclines. Mammalian cells contain two isoforms of topo II (alpha and beta) and the TARDIS assay enables visualisation of isoform-specific complexes. Drug-treated cells were embedded in agarose, lysed and incubated with anti-topo II antibodies to microscopically detect topo IIalpha or beta complexes. Results for K562 cells (at clinically relevant concentrations) showed that IDA and idarubicinol, its metabolite, formed mainly topo IIalpha cleavable complexes, the level of which decreases at doses > 1 microM for IDA. Our data suggest that this decrease is due to catalytic inhibition by IDA at these doses. Doxorubicin formed low levels of topo IIalpha complexes and negligible topo IIbeta complexes. In cytotoxicity studies, IDA and idarubicinol were equipotent, but both were more potent than daunorubicin and doxorubicin. We showed for the first time that there was a persistent increase in levels of topo IIalpha cleavable complexes after removal of IDA, suggesting that its greater effectiveness may be associated with both the longevity and high levels of these complexes.
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PMID:Formation and longevity of idarubicin-induced DNA topoisomerase II cleavable complexes in K562 human leukaemia cells. 1203 65

The human U-1285 and GLC(4) cell lines, both derived from small cell carcinoma of the lung, are present in doxorubicin-sensitive (U-1285 and GLC(4)) and doxorubicin-resistant MRP-expressing (U-1285dox and GLC(4)/ADR) variants. These sublines were examined here with respect to their susceptibilities to the toxic effects of selenite and compared to the toxic effects of selenite on the promyelocytic leukemia cell line HL-60 and its doxorubicin-resistant P-glycoprotein expressing variant. The drug-resistant U-1285dox and GLC(4)/ADR sublines proved to be 3- and 4-fold, respectively, more sensitive to the cytotoxicity of selenite than the drug-sensitive U-1285 and GLC(4) sublines, whereas no difference was observed between the HL-60 sublines. The presence of doxorubicin at a concentration equal to the IC(10) did not significantly potentiate the toxic effects of selenite. The presence of selenite did not significantly affect the expression of the multi-drug resistant proteins (MRP1, LRP and topoisomerase IIalpha) in the drug-resistant cells. The activities of thioredoxin reductase (TrxR) were higher (50 and 25%, respectively) in the drug resistant cell sublines U-1285dox and GLC(4)/ADR compared to the drug-sensitive parental lines. The activity of glutathione reductase (GR) was essentially the same in the drug-sensitive and -resistant cell lines. Exposure to selenite resulted in a 4-fold increase in both TrxR and GR activities in U-1285 cells, an effect, which was less pronounced in the presence of doxorubicin. Under similar conditions the increase in the TrxR activity in the resistant U-1285dox cell line, was only 30% and the activity of GR was unaltered. Different responses in the activity of the key enzymes in selenium metabolism are one possible mechanism explaining the differential cytotoxicity of selenium in these cells.
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PMID:Drug-resistant human lung cancer cells are more sensitive to selenium cytotoxicity. Effects on thioredoxin reductase and glutathione reductase. 1203 72

There is little information on the pharmacokinetics and pharmacodynamics of doxorubicin (DXR) administered during locoregional treatments of colon carcinoma under hyperthermic conditions. The aim of this study was to evaluate distribution and activity of DXR in healthy tissue and tumor tissues under hyperthermic conditions by using an experimental model of ex vivo isolated vascular perfusion of human colon segments bearing primary carcinoma. The influence of topoisomerase-II alpha (TPI2 alpha) expression on the anti-cancer activity of DXR combined with heat was evaluated as well. Twenty seven colon segments surgically resected for primary carcinoma were perfused ex vivo under physiological conditions (group A, n = 7), with DXR (group B, n = 6), under hyperthermic conditions (group C, n = 6), and with the combination DXR-hyperthermia (group D, n = 8). Samples of perfusate and tissues (normal and pathologic) were collected during 90 minutes of perfusion. Doxorubicin concentration in perfusate and tissues was assessed with high-performance liquid chromatography. Protein expression of TPI2 alpha, the main molecular target of DXR, was measured by image analysis in normal mucosa and tumor samples. Drug uptake was increased by heat equally in healthy and diseased tissue. Under hyperthermic conditions, DXR activity was significantly higher in pathologic mucosa than in normal mucosa. Furthermore, the activity of DXR combined with heat correlated with baseline TPI2 alpha levels in tumor tissue. From these findings, it appears that heat sensitizes tumor cells-but not normal mucosa-to DXR activity. Furthermore, protein levels of TPI2 alpha in pretreatment samples could predict tumor sensitivity to DXR.
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PMID:Doxorubicin activity is enhanced by hyperthermia in a model of ex vivo vascular perfusion of human colon carcinoma. 1273 80

New active drugs are needed for the treatment of primary brain tumors in both children and adults. S16020 is a cytotoxic olivacine derivative that inhibits topoisomerase II. The aim of the study was to determine its antitumor activity in athymic mice bearing subcutaneous medulloblastoma (IGRM33, 34, 57) and glioblastoma (IGRG88, 93, 121) xenografts treated at an advanced stage of tumor growth in comparison with that of doxorubicin. Animals were randomly assigned to receive i.v. S16020 or doxorubicin weekly for three consecutive weeks. The optimal dose was 80 mg/kg per week. S16020 demonstrated a significant antitumor activity in two out of three medulloblastoma xenografts. IGRM57 xenografts were highly sensitive with 100% tumor regressions and a tumor growth delay (TGD) of 102 days, while one of eight IGRM34 xenografts showed a partial regression with a TGD of 16 days. Doxorubicin was significantly more active than S16020 in these two models. IGRM33, a model established from a tumor in relapse after chemotherapy and radiotherapy, was refractory to both drugs. S16020 demonstrated a significant antitumor activity in the three glioblastoma xenografts evaluated. The wild-type p53 IGRG93 xenograft was highly sensitive with 100% tumor regressions and a TGD of 54 days. IGRG121 (wt p53) and IGRG88 (mutant p53) were moderately sensitive with TGDs of 33 and 23 days, respectively. Doxorubicin showed greater activity in two of these models. All six xenografts exhibited low expression of mdr1 as quantitated by RT-PCR, and no correlation was found with the activity of either drug. Conversely, a low activity of the two drugs was significantly associated with a high expression of MRP1 in medulloblastomas. Finally, no relationship was observed between drug sensitivity to either drug and expression of their target, topoisomerase IIalpha. In conclusion, S16020 and doxorubicin showed significant antitumor activity in brain tumor xenografts treated at an advanced stage of tumor growth. Their activity was related to MRP1 expression in medulloblastomas.
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PMID:In vivo antitumor activity of S16020, a topoisomerase II inhibitor, and doxorubicin against human brain tumor xenografts. 1273 60

Salvicine, a novel topoisomerase II inhibitor and a diterpenoid quinone compound, exerts potent in vitro and in vivo antitumor effects. In our study, we show that salvicine effectively kills multidrug-resistant (MDR) sublines, such as K562/A02, KB/VCR and MCF-7/ADR, and parental K562, KB and MCF-7 cell lines to an equivalent degree. These cytotoxic activities of salvicine were much more potent than those of several classical anticancer drugs (average resistance factor: 1.42 for salvicine vs. 344.35, 233.19 and 71.22 for vincristine, doxorubicin and etoposide, respectively). Flow cytometry and DNA agarose gel electrophoresis demonstrated that salvicine induced similar levels of apoptosis in MDR K562/A02 and parental cells. The compound activated caspase-1 and -3 (but not caspase-8) and increased the ratio of bax to bcl-2 mRNA via reduction of bcl-2 mRNA expression in the same cells. Furthermore, salvicine induced the downregulation of mdr-1 gene and P-gp expression but had no effect on MRP and LRP gene expression in MDR K562/A02 cells. These results suggest that the reduction of mdr-1 and bcl-2 expression by salvicine possibly contributes to its cytotoxicity and apoptotic induction in this system. The effectiveness, broad-spectrum activity and possibly novel mechanism of killing MDR tumor cells in vitro of salvicine signify promising in vivo and clinical activity. The novel chemical structure of this compound further implies a role for salvicine in future MDR tumor therapy.
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PMID:Cytotoxicity, apoptosis induction and downregulation of MDR-1 expression by the anti-topoisomerase II agent, salvicine, in multidrug-resistant tumor cells. 1279 65

Doxorubicin (DOX) is a DNA topoisomerase II inhibitor widely used in anticancer treatment, however, it can lead to irreversible cardiac damage with severe debilitation. TBP-binding associated factor 1 (TAF1) is increased in DOX damaged hearts in vivo and in cardiomyocytes in vitro. To identify the functional role for TAF1 in DOX-treated heart we overexpressed wild type and mutant TAF1 in H9c2 cells. Overexpression of wild-type TAF1, but not N-terminal kinase domain mutants, increased tolerance to DOX in confluent cells. DOX treatment can cause prolonged G1 arrest. We found increased cdk2 activity coupled to increased cyclin E protein and decreased p21(waf1Cip1) and p27(Kip1) protein to correlate only with increased DOX tolerance and wild-type TAF1. DOX sensitivity was restored when the cdk2-inhibitor Roscovitine was co-administered with DOX. Overexpression of cdk2-alone increased resistance to DOX. Thus, TAF1 induced DOX tolerance in confluent cells through an increase in cdk2 activity is directed by the TAF1 N-terminal domain. These studies suggest new avenues for myocardial protection against DOX toxicity and suggest a role for cdk2 in chemorefractory cells.
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PMID:TBP-associated factor 1 overexpression induces tolerance to Doxorubicin in confluent H9c2 cells by an increase in cdk2 activity and cyclin E expression. 1512 10

Despite the increased survival rates of osteosarcoma patients attributed to adjuvant chemotherapy, at least one third of the patients still die due to their disease. Further improvements in the management of osteosarcoma may rely on a more individualised treatment strategy, as well as on the introduction of new drugs. To aid in the preclinical evaluation of new candidate substances against osteosarcoma, we have established 11 human osteosarcoma xenograft lines and characterised them with regard to response to five different reference drugs. Doxorubicin, cisplatin methotrexate, ifosfamide and lomustine were effective in 3/11, 3/11, 1/10, 5/11 and 4/11 of the xenografts, respectively. Five xenografts were resistant to all compounds tested. We also assessed the mRNA expression levels of the xenografts for the O(6)-Methylguanine DNA Methyltransferase (MGMT), DNA topoisomerase II- (Topo II)-alpha, Gluthathione-S-transferase (GST)-pi, Multidrug-resistance related protein (MRP) 1 and Multidrug-resistance (MDR) 1 genes. There was an inverse correlation between the transcript levels of GST-pi and doxorubicin growth inhibition (r=-0.66; p<0.05), and between the transcript levels of MGMT and the effect of lomustine (r=-0.72; p<0.01), whereas the expression of MRP1 and cisplatin growth inhibition was positively correlated (r=0.82; p<0.005). This panel of xenografts should constitute a good tool for pharmacological and molecular studies in osteosarcoma.
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PMID:Human osteosarcoma xenografts and their sensitivity to chemotherapy. 1544 48


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