Explore chapters and articles related to this topic
Chemotherapy in pregnancy
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Topoisomerase I and II are involved in the cleaving of DNA strands for the purpose of replication. Topoisomerase inhibitors bind to the DNA–topoisomerase complex and prevent the advancement of the replication fork. Topotecan and irinotecan are examples of compounds specific to topoisomerase I, while etoposide binds specifically to the topoisomerase II–DNA complex.
Cancer Research Is Leading the Way
Published in Rebecca A. Krimins, Learning from Disease in Pets, 2020
DNA topoisomerase 1 (TOP1) is an enzyme that induces single strand breaks in supercoiled DNA permitting relaxation and remodeling, which is essential for transcription, replication, and repair. TOP1 is dysregulated in a variety of cancers. Two TOP1 inhibitors, irinotecan and topotecan, have been FDA approved for use in ovarian, small cell-lung, cervical, colorectal, and/or gastric cancers (Pommier 2006). Both FDA-approved TOP1 inhibitors are in the camptothecin class, and these compounds have significant limitations including chemical instability, short half-life, susceptibility to efflux mediated drug-resistance, and dose-limiting diarrhea (Burton et al. 2018). To bypass these limitations, novel chemical classes of TOP1 inhibitors have been developed. The indenoisoquinoline class of TOP1 inhibitors is one alternate class of compounds which displays nanomolar potency and has enhanced chemical stability and drug efflux properties (Burton et al. 2018). Three indenoisoquinoline TOP1 inhibitors with varying pharmacokinetic properties were examined in a comparative oncology trial in dogs with NHL. While all three compounds displayed objective therapeutic activity, a single compound was identified as having significantly enhanced tumor accumulation and retention relative to the others (Burton et al. 2018). This trial demonstrated not only that indenoisoquinoline TOP1 inhibitors may be therapeutically relevant in the treatment of canine NHL, but importantly also allowed for identification of a clinical lead compound, LMP744, that is currently under evaluation in human clinical trials (Burton et al. 2018).
Herbs in Cancer Therapy
Published in Anil K. Sharma, Raj K. Keservani, Surya Prakash Gautam, Herbal Product Development, 2020
Annum Malik, Shahzadi Sidra Saleem, Kifayat Ullah Shah, Learn-Han Lee, Bey Hing Goh, Tahir Mehmood Khan
Inhibition of topoisomerase plays a pivotal role in the treatment of cancer. Several herbal drugs are shown to be efficacious in controlling the activity of topoisomerase. Some of these herbal drugs includes Camptothecins inhibiting topoisomerase I while epopodo phylotoxins show anticancer activity by inhibiting topoisomerase II (Nobili et al. 2009). Etoposide inhibit topoisomerase II (Topo II), enzyme that produce transient double strand breaks in the DNA. Etoposide stabilizes a complex of the Topo II enzyme with cleaved DNA, inducing permanent breaks in the DNA and triggering cell death (Baldwin and Osheroff 2005).
Novel topoisomerase II/EGFR dual inhibitors: design, synthesis and docking studies of naphtho[2′,3′:4,5]thiazolo[3,2-a]pyrimidine hybrids as potential anticancer agents with apoptosis inducing activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Mai A. E. Mourad, Ayman Abo Elmaaty, Islam Zaki, Ahmed A. E. Mourad, Amal Hofni, Ahmed E. Khodir, Esam M. Aboubakr, Ahmed Elkamhawy, Eun Joo Roh, Ahmed A. Al-Karmalawy
DNA topoisomerases are essential nuclear enzymes that maintain the topological changes of DNA and play key role in catalysing DNA replication, proliferation, transcription, recombination, repair, chromosome condensation and segregation4,7,8. Additionally, most of available anticancer regimens based on using at least one member of topoisomerase inhibitors6. However, DNA topoisomerases are generally classified into topoisomerase I (topo I) and topoisomerase II (topo II)9. Topo I possesses its functions by cleaving only one strand of DNA, while type II cleaves both DNA strands10. In the same context, topo II catalysis requires two cofactors ATP and Mg+2 in order to carry out its double-stranded DNA passage reaction11.
Design, synthesis, and biological evaluation of novel ciprofloxacin derivatives as potential anticancer agents targeting topoisomerase II enzyme
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Hadeer K. Swedan, Asmaa E. Kassab, Ehab M. Gedawy, Salwa E. Elmeligie
DNA topological problems arise from the intertwined nature of the DNA double helix structure, which causes tangles and supercoiling of the DNA duplex during the DNA replication and transcription. DNA supercoiling results in torsion that impair the function of DNA or RNA polymerases. Type II topoisomerase enzyme (Topo II) prevents and corrects these types of topological problems via transient double-stranded breaks, causing DNA metabolism to proceed, allowing the cell to efficiently replicate so enabling cellular division and vitality5–7. The role of divalent Mg2+ ions in Topo II-mediated reactions was recognised as an implication in enzyme-mediated DNA cleavage reactions. (2) participation in ATPase reactions and functions by providing the enzyme with magnesium–ATP substrate8. Topo II enzyme inhibition leads to apoptosis and cell death9,10, therefore, it is considered a valid strategy in cancer therapy. The presence of topoisomerase enzyme in both mammalian and bacterial cells makes it a pronounced target for antibacterial and anticancer drugs10,11. Recently, mammalian Topo II is considered a critical target for anticancer drug development12–14.
Topo II inhibition and DNA intercalation by new phthalazine-based derivatives as potent anticancer agents: design, synthesis, anti-proliferative, docking, and in vivo studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mohamed M. Khalifa, Ahmed A. Al-Karmalawy, Eslam B. Elkaeed, Mohamed S. Nafie, Mohamed A. Tantawy, Ibrahim H. Eissa, Hazem A. Mahdy
Seven compounds that exhibited significant DNA binding affinities (8a, 8b, 9a, 9c, 9d, 14a, and 14b) were further estimated to determine their inhibitory activities towards topoisomerase II. The activity of topoisomerase II was determined according to the reported procedure described by Patra et al.42. Doxorubicin was utilised as a positive control in this test. The results were reported as IC50 values and summarised in Table 2. Compounds 8b, 9d, and 14a was found to be the most potent derivatives with IC50 values of 8.91 ± 0.77, 7.02 ± 0.54, and 7.64 ± 0.66 µM, which were more active than the reference drug, doxorubicin (IC50 = 9.65 ± 0.77 µM). The other tested compounds, 8a, 9a, 9c, and 14 b, exhibited moderate to weak activities with high IC50 values ranging from 13.66 ± 1.02 to 13.66 ± 1.02 µM.