Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.3 (topoisomerase)
 9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nuclear enzyme DNA topoisomerase II is a major target for antineoplastic agents. All topoisomerase II-directed agents are able to interfere with at least one step of the catalytic cycle. Agents able to stabilize the covalent DNA topoisomerase II complex (also known as the cleavable complex) are traditionally called topoisomerase II poisons, while agents acting on any of the other steps in the catalytic cycle are called catalytic inhibitors. Thus, catalytic topoisomerase II inhibitors are a heterogeneous group of compounds that might interfere with the binding between DNA and topoisomerase II (aclarubicin and suramin), stabilize noncovalent DNA topoisomerase II complexes (merbarone, ICRF-187, and structurally related bisdioxopiperazine derivatives), or inhibit ATP binding (novobiocin). Some, such as fostriecin, may also have alternative biological targets. Whereas topoisomerase II poisons are used solely for their antitumor activities, catalytic inhibitors are utilized for a variety of reasons, including their activity as antineoplastic agents (aclarubicin and MST-16), cardioprotectors (ICRF-187), or modulators in order to increase the efficacy of other agents (suramin and novobiocin). In this review, the mechanism and biological activity of different catalytic inhibitors is described, with emphasis on therapeutically used compounds. We will then discuss future development and applications of this interesting class of compounds.
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PMID:Catalytic topoisomerase II inhibitors in cancer therapy. 1288 11

Bisdioxopiperazine (Biz) compounds, including ICRF-154 and razoxane (ICRF-159, Raz), are anticancer agents developed in the UK specifically targeting tumor metastases. Further three bisdioxopiperazine derivatives, bimolane (Bim), probimane (Pro) and MST-16, have been synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, PR China after 1980. Since metastases, the prevailing deadliest pathologic feature of cancer in clinics, have been the main obstacle in cancer therapy, antimetastatic effects and mechanisms of Biz compounds are interesting and significant topics of all time for researchers undergoing the investigations of metastases biology, treatments and patho-physiology. This review addresses and highlights the different inhibitions against metastases in vivo and molecular mechanisms in vitro of Biz compounds especially relating to the inhibitions of tumor metastasis including pathways of inhibitions against angiogenesis, topoisomerase II, calmodulin, sialic acid, fibrinogen, cell-movement and so on. We argue hererin that the systematic exploration of antimetastatic activity and mechanisms of Biz compounds seems to be a shortcut for a final solution of cancer therapy in the future.
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PMID:Antimetastatic activities and mechanisms of bisdioxopiperazine compounds. 2095 Feb 58

Anthracyclines (such as doxorubicin or daunorubicin) are among the most effective anticancer drugs, but their usefulness is hampered by the risk of irreversible cardiotoxicity. Dexrazoxane (ICRF-187) is the only clinically approved cardioprotective agent against anthracycline cardiotoxicity. Its activity has traditionally been attributed to the iron-chelating effects of its metabolite with subsequent protection from oxidative stress. However, dexrazoxane is also a catalytic inhibitor of topoisomerase II (TOP2). Therefore, we examined whether dexrazoxane and two other TOP2 catalytic inhibitors, namely sobuzoxane (MST-16) and merbarone, protect cardiomyocytes from anthracycline toxicity and assessed their effects on anthracycline antineoplastic efficacy. Dexrazoxane and two other TOP2 inhibitors protected isolated neonatal rat cardiomyocytes against toxicity induced by both doxorubicin and daunorubicin. However, none of the TOP2 inhibitors significantly protected cardiomyocytes in a model of hydrogen peroxide-induced oxidative injury. In contrast, the catalytic inhibitors did not compromise the antiproliferative effects of the anthracyclines in the HL-60 leukemic cell line; instead, synergistic interactions were mostly observed. Additionally, anthracycline-induced caspase activation was differentially modulated by the TOP2 inhibitors in cardiac and cancer cells. Whereas dexrazoxane was upon hydrolysis able to significantly chelate intracellular labile iron ions, no such effect was noted for either sobuzoxane or merbarone. In conclusion, our data indicate that dexrazoxane may protect cardiomyocytes via its catalytic TOP2 inhibitory activity rather than iron-chelation activity. The differential expression and/or regulation of TOP2 isoforms in cardiac and cancer cells by catalytic inhibitors may be responsible for the selective modulation of anthracycline action observed.
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PMID:Catalytic inhibitors of topoisomerase II differently modulate the toxicity of anthracyclines in cardiac and cancer cells. 2411 35

Telomere maintenance by telomerase activity supports the infinite growth of cancer cells. MST-312, a synthetic telomerase inhibitor, gradually shortens telomeres at non-acute lethal doses and eventually induces senescence and apoptosis of telomerase-positive cancer cells. Here we report that MST-312 at higher doses works as a dual inhibitor of telomerase and DNA topoisomerase II and exhibits acute anti-proliferative effects on cancer cells and xenografted tumours in vivo. Our cell-based chemical fingerprinting approach revealed that cancer cells with shorter telomeres and lower expression of lamin A, a nuclear architectural protein, exhibited higher sensitivity to the acute deleterious effects of MST-312, accompanied by formation of telomere dysfunction-induced foci and DNA double-strand breaks. Telomere elongation and lamin A overexpression attenuated telomeric and non-telomeric DNA damage, respectively, and both conferred resistance to apoptosis induced by MST-312 and other DNA damaging anticancer agents. These observations suggest that sufficient pools of telomeres and a nuclear lamina component contribute to the cellular robustness against DNA damage induced by therapeutic treatment in human cancer cells.
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PMID:Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells. 3028 51


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