Topoisomerase II Inhibitors in Cancer Treatment

2011 ◽  
Vol 3 (4) ◽  
pp. 1173-1181
Author(s):  
Devendra Singh Thakur
Keyword(s):  
Anticancer Agents ◽  
Topoisomerase Ii ◽  
Double Helix ◽  
Clinical Use ◽  
Topoisomerase Inhibitors ◽  
Dna Double Strand Breaks ◽  
Metabolic Processes ◽  
Strand Breaks ◽  
Cellular Target ◽  
Dna Double Helix

Topoisomerase II constitutes a family of nuclear enzymes essential to all living cells. These enzymes are capable of transferring one DNA double helix through a transient break in another DNA double helix. Type II topoisomerases play important roles in DNA metabolic processes, in which they are involved in DNA replication, transcription, chromosome condensation and de-condensation. Topoisomerase II is also the cellular target for a number of widely used anticancer agents currently in clinical use, such as the anthracyclines (daunorubicin and doxorubicin), the epipodophyllotoxins (etoposide and teniposide), and the aminoacridines. These agents stimulate the topoisomerase II-cleavable complex, which is a transient configuration of topoisomerase II on DNA in which topoisomerase II is covalently attached to DNA. This causes the accumulation of cytotoxic nonreversible DNA double-strand breaks generated by the processing of such complexes by DNA metabolic processes. As of present, the clinical use of catalytic topoisomerase inhibitors as antineoplastic agents is limited to aclarubicin and MST-16. Both of these compounds are preferentially active toward hematological malignancies and show limited activity toward solid tumors. This review explains the role of topoisomerase inhibitors in cancer therapy.

scholarly journals Topoisomerases as anticancer targets

2018 ◽  
Vol 475 (2) ◽  
pp. 373-398 ◽  
Author(s):  
Justine L. Delgado ◽  
Chao-Ming Hsieh ◽  
Nei-Li Chan ◽  
Hiroshi Hiasa
Keyword(s):  
Anticancer Drugs ◽  
Anticancer Agents ◽  
Topoisomerase Ii ◽  
Therapeutic Targets ◽  
Strand Break ◽  
Cancer Type ◽  
Topoisomerase Inhibitors ◽  
Topoisomerase Ii Poisons ◽  
Topoisomerase Poisons ◽  
Replication Fork Arrest

Many cancer type-specific anticancer agents have been developed and significant advances have been made toward precision medicine in cancer treatment. However, traditional or nonspecific anticancer drugs are still important for the treatment of many cancer patients whose cancers either do not respond to or have developed resistance to cancer-specific anticancer agents. DNA topoisomerases, especially type IIA topoisomerases, are proved therapeutic targets of anticancer and antibacterial drugs. Clinically successful topoisomerase-targeting anticancer drugs act through topoisomerase poisoning, which leads to replication fork arrest and double-strand break formation. Unfortunately, this unique mode of action is associated with the development of secondary cancers and cardiotoxicity. Structures of topoisomerase–drug–DNA ternary complexes have revealed the exact binding sites and mechanisms of topoisomerase poisons. Recent advances in the field have suggested a possibility of designing isoform-specific human topoisomerase II poisons, which may be developed as safer anticancer drugs. It may also be possible to design catalytic inhibitors of topoisomerases by targeting certain inactive conformations of these enzymes. Furthermore, identification of various new bacterial topoisomerase inhibitors and regulatory proteins may inspire the discovery of novel human topoisomerase inhibitors. Thus, topoisomerases remain as important therapeutic targets of anticancer agents.

scholarly journals MRN, CtIP, and BRCA1 mediate repair of topoisomerase II–DNA adducts

2016 ◽  
Vol 212 (4) ◽  
pp. 399-408 ◽  
Author(s):  
Tomas Aparicio ◽  
Richard Baer ◽  
Max Gottesman ◽  
Jean Gautier
Keyword(s):  
Dna Adducts ◽  
Topoisomerase Ii ◽  
Nonhomologous End Joining ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Homology Directed Repair ◽  
Egg Extracts ◽  
Additional Processing ◽  
Special Challenge

Repair of DNA double-strand breaks (DSBs) with complex ends poses a special challenge, as additional processing is required before DNA ligation. For example, protein–DNA adducts must be removed to allow repair by either nonhomologous end joining or homology-directed repair. Here, we investigated the processing of topoisomerase II (Top2)–DNA adducts induced by treatment with the chemotherapeutic agent etoposide. Through biochemical analysis in Xenopus laevis egg extracts, we establish that the MRN (Mre11, Rad50, and Nbs1) complex, CtIP, and BRCA1 are required for both the removal of Top2–DNA adducts and the subsequent resection of Top2-adducted DSB ends. Moreover, the interaction between CtIP and BRCA1, although dispensable for resection of endonuclease-generated DSB ends, is required for resection of Top2-adducted DSBs, as well as for cellular resistance to etoposide during genomic DNA replication.

scholarly journals Author response: Post-meiotic DNA double-strand breaks occur in Tetrahymena, and require Topoisomerase II and Spo11

2017 ◽  
Author(s):  
Takahiko Akematsu ◽  
Yasuhiro Fukuda ◽  
Jyoti Garg ◽  
Jeffrey S Fillingham ◽  
Ronald E Pearlman ◽  
...  
Keyword(s):  
Topoisomerase Ii ◽  
Double Strand Breaks ◽  
Author Response ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Response Post

Induction of DNA double-strand breaks by 8-methoxycaffeine: cell cycle dependence and comparison with topoisomerase II inhibitors

1994 ◽  
Vol 15 (11) ◽  
pp. 2491-2496 ◽  
Author(s):  
Patrizia Russo ◽  
Guido Cimoli ◽  
Monica Valenti ◽  
Fabio De Sessa ◽  
Silvio Parodi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Topoisomerase Ii ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Topoisomerase Ii Inhibitors ◽  
Cell Cycle Dependence ◽  
Cycle Dependence

scholarly journals BRCA1- and BRCA2-Deficient Cells Are Sensitive to Etoposide-Induced DNA Double-Strand Breaks via Topoisomerase II

2007 ◽  
Vol 67 (15) ◽  
pp. 7078-7081 ◽  
Author(s):  
Alejandro D. Treszezamsky ◽  
Lisa A. Kachnic ◽  
Zhihui Feng ◽  
Junran Zhang ◽  
Chake Tokadjian ◽  
...  
Keyword(s):  
Topoisomerase Ii ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Brca1 And Brca2 ◽  
Strand Breaks

scholarly journals MUTABLE R-NAVAJO ALLELES OF CYCLIC ORIGIN IN MAIZE

Genetics ◽  
1973 ◽  
Vol 73 (2) ◽  
pp. 273-296
Author(s):  
R Alexander Brink ◽  
Elizabeth Williams
Keyword(s):  
Nucleotide Sequence ◽  
Gene Action ◽  
Double Helix ◽  
Donor Site ◽  
Chromosome Breakage ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Unstable Compound ◽  
The Stability ◽  
Dna Double Helix

ABSTRACT The generation in cyclic fashion of 26 mutable R-Navajo (mRnj) alleles in maize involved transposition of a non-specific repressor of gene action, Modulator (Mp), first away from, and then back to, the R locus represented by the R-Navajo (Rnj) all ele on chromosome 10. The mPnj alleles reconstituted in this way vaned widely, and continuously, in mutability to Rnj-that is, in transposition of Mp away from the R locus, thus derepressing the Rnj gene. They were alike, or nearly so, however, in activating Ds chromosome breakage and in increasing the stability of variegated pericarp, another unstable compound allele comprising Mp conjoined with Prr on chromosomal 1. These latter two phenomena are based primarily on loci elsewhere in the genome. It is postulated that the 26 reconstituted mRnj alleles carry a common Mp which, however, is intercalated at a different site within each allele. Nucleotide sequence in the regions adjacent to Mp is assumed to determine the frequency with which a form of micro-nondisjunction occurs whereby Mp is released from a donor site. Transposition to a new site is interpreted in terms of a chromosome model that gives effect to nicking, or single strand breaks, occurring throughout the genome as a prerequisite to unwinding, strand separation, and replication, of the DNA double helix.

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