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)

In order to investigate the mechanisms of drug resistance arising in tumor cells, we investigated the capacity of fluoroquinolones to inhibit the in vitro growth of WEHI-3B monomyelocytic leukemia cells and then we established a variant of this line (currently maintained in the absence of drug). The line, named WEHI-3B/CPX, expresses a specific resistance to ciprofloxacin (CPX; resistance index=17.3+/-2.2), and does not show cross-resistance with other fluoroquinolones, camptothecin and topoisomerase II inhibitors such as doxorubicin, etoposide and teniposide. Although a little decrease in intracellular accumulation of CPX is observed in WEHI-3B/CPX cells, these cells do not express MDR or LRP markers, and the resistance is not circumvented by verapamil. Purified nuclear extracts from WEHI-3B and WEHI-3B/CPX cells were tested for topoisomerase I catalytic activity and checking in vitro topoisomerase I sensitivity to CPX and camptothecin inhibition, but no difference was observed. As the treatment with CPX showed that the resistant cell line suffers a significantly lower number of breaks in the DNA molecule we also addressed our investigations to the topoisomerase II-dependent DNA cleavage that, in the resistant clone, was found dramatically less susceptible to be enhanced by CPX both in pre-strand and post-strand DNA passage conditions. WEHI-3B/CPX cells do not express any character of multidrug resistance and represent a rare case of specific drug resistance to CPX. The specific resistance to CPX observed in these cells is related to a functional decrease of topoisomerase II cleavage activity. It could be consequent to a decreased binding affinity of CPX for the topoisomerase II--DNA complex or to a decreased affinity or specificity of topoisomerase II for its DNA cleavage sites.
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PMID:Altered DNA-cleavage activity of topoisomerase II from WEHI-3B leukemia cells with specific resistance to ciprofloxacin. 1139 72

Introduction: Topoisomerase II inhibitors have long been used in the frontline and as salvage therapy for AML, with daunorubicin and idarubicin being prototypical agents in this therapeutic class, classically in combination with nucleoside analogs, e.g. cytarabine. Most recently, several other compounds from this drug class have or are being investigated. Areas covered: The current paper reviews older and newer topoisomerase II inhibitors in clinical development for the treatment of AML. The authors discuss the clinical use of these agents, current trials involving them as well as their safety profile. Important side effects of these medications including therapy-related AML (t-AML) are also covered. Expert opinion: Topoisomerase II inhibitors have helped improve outcomes in AML. Recently, the FDA approved several agents including CPX-351 for the treatment of secondary and t-AML. CPX-351 may have applicability in other high-risk myeloid diseases. Future directions include a combination of these agents with other targeted therapies. Finally, the authors believe that small molecule inhibitors, such as venetoclax and possibly immunotherapy options could also be incorporated to our treatment paradigm in selected patients.
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PMID:Topoisomerase II inhibitors in AML: past, present, and future. 3113 13