Topoisomerase II Inhibitors: Current Use and Prospects

Mir, Olivier; Dahut, William; Goldwasser, François; Heery, Christopher R.

doi:10.1007/978-1-4614-0323-4_13

Cited by 3 publications

(8 citation statements)

References 141 publications

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“…Epirubicin is used in breast, esophageal and gastric cancers. 79 The molecular pharmacology and mechanism of action of anthracyclines are complex. In addition to their anti-Top2 activity, anthracyclines are potent DNA intercalators and generate reactive oxygen intermediates.…”

Section: Anticancer Top2-targeted Drugsmentioning

confidence: 99%

“…Its reduced potential to undergo redox reactions compared to doxorubicin may explain its reduced cardiotoxicity. 78 It is used in first line therapy for pediatric and adult acute leukemia 79 and second line therapy for breast, prostate cancers and hematological malignancies. 79 Mitoxantrone is also approved for worsening forms of multiple sclerosis since 2000.…”

Section: Anticancer Top2-targeted Drugsmentioning

confidence: 99%

“…78 It is used in first line therapy for pediatric and adult acute leukemia 79 and second line therapy for breast, prostate cancers and hematological malignancies. 79 Mitoxantrone is also approved for worsening forms of multiple sclerosis since 2000. Mitoxantrone has to be used with caution because of its risks of cardiotoxicity and secondary leukemia in relationship with Top2β poisoning.…”

Section: Anticancer Top2-targeted Drugsmentioning

confidence: 99%

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Drugging Topoisomerases: Lessons and Challenges

2013

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Topoisomerases are ubiquitous enzymes that control DNA supercoiling and entanglements. They are essential during transcription and replication and topoisomerase inhibitors are among the most effective and most commonly used anticancer and antibacterial drugs. This review consists in two parts. In the first part (“Lessons”), it gives background information on the catalytic mechanisms of the different enzyme families (6 different genes in humans and 4 in most bacteria), describes the “interfacial inhibition” by which topoisomerase-targeted drugs act as topoisomerase poisons and describes clinically relevant topoisomerase inhibitors. It generalizes the interfacial inhibition principle, which was discovered from the mechanism of action of topoisomerase inhibitors, and discusses how topoisomerase inhibitors kill cells by trapping topoisomerases on DNA rather than by classical enzymatic inhibition. Trapping protein-DNA complexes extends to a novel mechanism of action of PARP inhibitors and could be applied to the targeting of transcription factors. The second part of the review focuses on the challenges for discovery and precise use of topoisomerase inhibitors, including targeting topoisomerase inhibitors using chemical coupling and encapsulation for selective tumor delivery, use of pharmacodynamic biomarkers to follow drug activity, complexity of the response determinants for anticancer activity and patient selection, prospects of rational combinations with DNA repair inhibitors targeting tyrosyl-DNA-phosphodiesterases 1 and 2 (TDP1 and TDP2) and PARP, and the unmeet need to develop inhibitors for type IA enzymes.

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Section: Anticancer Top2-targeted Drugsmentioning

confidence: 99%

Section: Anticancer Top2-targeted Drugsmentioning

confidence: 99%

Section: Anticancer Top2-targeted Drugsmentioning

confidence: 99%

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Drugging Topoisomerases: Lessons and Challenges

2013

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“…To overcome these, epirubicin (4′‐epi‐doxorubicin) was developed as an active isomer of doxorubicin with reduced cardiotoxicity. It was subsequently approved by FDA in 1999 for use in esophageal, gastric, and breast cancers . In similar efforts, anthracenedione, that is, mitoxantrone, was also developed as a synthetic analogue of anthracyclines and was approved by the FDA for the treatment of prostate cancer .…”

Section: Drugs Targeting Different Type II Topoisomerasesmentioning

confidence: 99%

“…It was subsequently approved by FDA in 1999 for use in esophageal, gastric, and breast cancers . In similar efforts, anthracenedione, that is, mitoxantrone, was also developed as a synthetic analogue of anthracyclines and was approved by the FDA for the treatment of prostate cancer . However, at high doses even mitoxantrone has been observed to exhibit risks of cardiotoxicity and secondary leukemia .…”

Section: Drugs Targeting Different Type II Topoisomerasesmentioning

confidence: 99%

Topoisomerases: Resistance versus Sensitivity, How Far We Can Go?

Bansal

Bajaj

Pandey

et al. 2016

Medicinal Research Reviews

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DNA topoisomerases are ubiquitously present remarkable molecular machines that help in altering topology of DNA in living cells. The crucial role played by these nucleases during DNA replication, transcription, and recombination vis-à-vis less sequence similarity among different species makes topoisomerases unique and attractive targets for different anticancer and antibacterial drugs. However, druggability of topoisomerases by the existing class of molecules is increasingly becoming questationable due to resistance development predominated by mutations in the corresponding genes. The current scenario facing a decline in the development of new molecules further comprises an important factor that may challenge topoisomerase-targeting therapy. Thus, it is imperative to wisely use the existing inhibitors lest with this rapid rate of losing grip over the target we may not go too far. Furthermore, it is important not only to design new molecules but also to develop new approaches that may avoid obstacles in therapies due to multiple resistance mechanisms. This review provides a succinct account of different classes of topoisomerase inhibitors, focuses on resistance acquired by mutations in topoisomerases, and discusses the various approaches to increase the efficacy of topoisomerase inhibitors. In a later section, we also suggest the possibility of using bisbenzimidazoles along with efflux pump inhibitors for synergistic bactericidal effects.

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Topoisomerase Ii Enzyme Inhibitors

Fırat¹,

Yildiz²

2020

Ankara Universitesi Eczacilik Fakultesi Dergisi

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Amaç: Son yıllarda önemi daha da artan topoizomeraz II enzim inhibitörleri'nin Farmasötik Kimya bilimi açısından ve klinik kullanımları değerlendirilmiştir. Bu bağlamda, klinik kullanımları olan bileşiklerin yanında geliştirilme aşamasında olan bazı bileşiklere de yer verilmiştir.Sonuç ve Tartışma: Topoizomeraz II enzimi inhibisyonu hedefli kanser kemoterapisi ve bu mekanizmaya uygun, aktivitesi yüksek olup advers etkileri az olan ilaç geliştirme çabaları uzun yıllardır devam eden bir süreçtir. Sonuç olarak, bitkisel veya sentetik olarak elde edilen topoizomeraz II inhibitörlerinin kimyasal yapıları üzerinde uygun modifikasyonların yapılması, yüksek aktivitede birçok yeni ajanın klinik kullanımını mümkün kılmaktadır. Ayrıca kanser hastalarında sıklıkla görülen ilaç direncinin önüne geçilmesi, hedefe yönelik tedavi ve toksisitelerin azaltılması yeni ajanların keşfiyle sağlanabilecektir.Yeni ajanların kullanımının bireyselleştirilmiş tedavi yöntemleri arasında bulunmasının sağlanması ile hastalara en uygun tedavi sunulabilecektir.

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Topoisomerase II Inhibitors: Current Use and Prospects

Cited by 3 publications

References 141 publications

Drugging Topoisomerases: Lessons and Challenges

Drugging Topoisomerases: Lessons and Challenges

Topoisomerases: Resistance versus Sensitivity, How Far We Can Go?

Topoisomerase Ii Enzyme Inhibitors

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