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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).
Drug Delivery
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Gudrun Fleischhack, Martin Garnett, Kévin Beccaria
The DNA topoisomerases I and II are critical for DNA function and cell survival; they are cellular targets for several antitumor drugs: camptothecin derivatives like irinotecan and topotecan interact with topoisomerase I, and epipodophyllotoxine derivatives, actinomycin D, anthracycline derivatives, mitoxantrone, and amsacrine interact with topoisomerase II. Drug–topoisomerase interaction which probably leads to antitumoral effect is a poisoning due to stabilization of cleavable complexes between the enzyme and DNA rather than a trivial inhibition of the enzyme. Cellular resistance to topoisomerase inhibitors is probably based on modification of the target (e.g., decreased ability to form the cleavable complex) or of the drug transport (e.g., overexpression of membrane P-gp).77
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.
A patent review of topoisomerase I inhibitors (2016–present)
Published in Expert Opinion on Therapeutic Patents, 2021
Asier Selas, Endika Martin-Encinas, Maria Fuertes, Carme Masdeu, Gloria Rubiales, Francisco Palacios, Concepción Alonso
DNA topoisomerases are DNA modifying enzymes that solve DNA topological stress originated in vital cell events such as replication, transcription or recombination. These enzymes accomplish this fact by means of a catalytic cycle which in all cases involves binding to the corresponding substrate (a double stranded DNA), followed by a nucleophilic attack to a DNA phosphodiester group by a catalytic tyrosine residue (cleavage step). This reaction results in a covalent topoisomerase-DNA cleavage complex (Topcc) that allows the strand passage. The mentioned transesterification is highly reversible and after strand passage, the hydroxyl group of the cleaved phosphodiester backbone performs a nucleophilic attack to the phosphotyrosyl bond (the inverse reaction to the cleavage), resulting in a religation of the DNA (religation step) and a subsequent releasing of the enzyme [8–11].
Analysis of plant-derived phytochemicals as anti-cancer agents targeting cyclin dependent kinase-2, human topoisomerase IIa and vascular endothelial growth factor receptor-2
Published in Journal of Receptors and Signal Transduction, 2021
Bishajit Sarkar, Md. Asad Ullah, Syed Sajidul Islam, MD. Hasanur Rahman, Yusha Araf
Due to the supercoiled structure of the DNA molecules, it is necessary to unwind the double-stranded DNA before replication, transcription, recombination, and other processes. DNA topoisomerases are the enzymes that function in unwinding, cutting, shuffling, and relegating the DNA double helix structure. The human genome encodes six topoisomerases that are grouped into three types: type Iα, type Iβ, and type IIα. DNA topoisomerase IIα is one of the necessary topoisomerases that function in various cellular functions. However, it is a genotoxic enzyme which can lead to cancer development. When DNA topoisomerase II cuts the double-stranded DNA, it may remain covalently attached to the broken end of the DNA. This reaction intermediate is known also as the cleavage complex. If the amount of the cleavage complex in the cell falls too much, then the cells are not able to divide into daughter cells due to mitotic failure, which results in the death of the cells. Moreover, if the amount of the cleavage complex increases too much, the temporary cleavage complex structures can become permanent double-stranded breaks in the DNA. These double-stranded breaks are caused by the faulty DNA tracking system which then initiates the faulty recombination and repair pathways of DNA replication and expression, leading to cancer (Figure 2). For this reason, DNA topoisomerase IIα is a potential target for anti-cancer drug development [77–81].