Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multidrug resistance (MDR) is associated with poor prognosis in leukemia, and anthracyclines, which are used in the treatment of leukemia, are associated with the expression of P-glycoprotein and the development of MDR. We report here that idarubicin, a new anthracycline approved for use in the treatment of acute myelogenous leukemia (AML), did not induce P-glycoprotein expression in the K562 human leukemia cell line under conditions where daunorubicin, doxorubicin and epirubicin did induce expression of P-glycoprotein. The P-glycoprotein expressing, multidrug resistant sublines developed to daunorubicin (K/DNR), doxorubicin (K/DOX) and epirubicin (K/EPR) were cross-resistant to the other anthracyclines and to vinblastine, taxol, colchicine and actinomycin D, but were not resistant to idarubicin or etoposide. The idarubicin treated subline, K/IDA, was only resistant to taxol but was 12-fold sensitized to etoposide, suggesting that idarubicin had affected topoisomerase II in this subline.
 ...
PMID:Development of drug resistance is reduced with idarubicin relative to other anthracyclines. 767 Jan 42

Relative to the commonly used anthracyclines, little is known about idarubicin and the development of multidrug resistance. We have previously shown the K562/IDA subline resulting from intermittent treatment of the K562 human leukaemia cell line with 20 ng/ml idarubicin did not develop multidrug resistance but became more sensitive to etoposide. Additional similar treatments of this subline produced the K562/IDA20 subline which partially retained its etoposide sensitivity although these cells expressed P-glycoprotein and were resistant to paclitaxel. Sensitization to etoposide was associated with increased decatenation activity of topoisomerase II, although there were no changes in topoisomerase IIalpha expression or formation of etoposide-dependent cleavable complexes. In comparison, the K562/IDA10 subline produced by intermittent treatment of the K562 cells, firstly with 5 ng/ml then 10 ng/ml idarubicin, showed no detectable expression of P-glycoprotein, decreased topoisomerase IIalpha expression and increased resistance to etoposide and amsacrine, but not to idarubicin or genistein. Even though intermittent treatment with idarubicin caused increased drug resistance in both sublines, they remained sensitive to idarubicin. Therefore the potential of idarubicin as a substitute for other anthracyclines in the treatment of cancer warrants further investigation.
 ...
PMID:Altered drug sensitivity in response to idarubicin treatment in K562 human leukaemia cells. 1044 67

Anthracyclines exert antitumor activity by stimulating site-selective DNA cleavage by topoisomerase II (top2). DNA cleavage sites stimulated by two anthracycline analogues, dh-EPI and da-IDA, were investigated at the histone gene cluster of cultured Drosophila Kc cells. The two agents stimulated analogue-specific patterns of double-stranded DNA cleavage in Kc cell chromatin. Analyses of 47 base sequences of dh-EPI sites showed that the analogue largely followed the in vitro selectivity rule, the requirement of (5')TA at 3' ends of cleaved strands. da-IDA was more selective than dh-EPI, and thus fewer sites could be collected. Nevertheless, base sequences were consistent with its in vitro base preferences. DNA cleavage was then studied in vitro with Drosophila and human top2 isoforms. The tested drugs stimulated distinct in vitro patterns that corresponded to the in vivo patterns. Human top2alpha promoted cleavage patterns that were much more similar to those of Drosophila top2 (both in vitro and in vivo) than human top2beta. Moreover, da-IDA showed a marked site-dependent preference for human top2beta. Thus, DNA site selection in vivo is different for the test anthracyclines, and together with a degree of beta-form specificity, may affect drug activity in human cells.
 ...
PMID:In vivo site specificity and human isoenzyme selectivity of two topoisomerase II-poisoning anthracyclines. 1091 49

Fludarabine (FLU, a fluorinated purine analog) and idarubicin (IDA, a DNA-topoisomerase II poison) are frequently used in cancer chemotherapy. The effects of these drugs on cultured normal human lymphocytes were studied to establish the possible involvement of chromosome damage in the apoptotic program. Chromosome aberrations (CA) were evaluated in first division metaphases and the apoptotic process was measured by morphological and electrophoretical techniques. The percentage of abnormal cells was increased from the doses of FLU 1.0 microg/ml and IDA 0.005 microg/ml (P<0.0001) with an important decrease in the mitotic index (MI) for the highest doses assayed. A significant dose-dependent induction of abnormal cells was observed for both drugs. An increase of apoptotic cells was found at 5.0 and 10.0 microg/ml of FLU (P<0.001) while IDA activated apoptosis at 0.05 microg/ml (P<0.01) and markedly from 0.1 microg/ml (P<0.001). These increments were dose dependent. Apoptotic cell morphology was associated with DNA fragmentation at the highest doses. The increased induction of abnormal cells and the decreased MI were in correlation with the apoptotic index for FLU and IDA, suggesting the role of CA in drug-induced cell death.
 ...
PMID:Correlation between chromosome damage and apoptosis induced by fludarabine and idarubicin in normal human lymphocytes. 1183 27