The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.
Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II
Open accessAbstract
Many intercalative antitumor drugs have been shown to induce reversible protein-linked DNA breaks in cultured mammalian cells. Using purified mammalian DNA topoisomerase II, we have demonstrated that the antitumor drugs ellipticine and 2-methyl-9-hydroxyellipticine (2-Me-9-OH-E+) can produce reversible protein-linked DNA breaks in vitro. 2-Me-9-OH-E+ which is more cytotoxic toward L1210 cells and more active against experimental tumors than ellipticine is also more effective in stimulating DNA cleavage in vitro. Similar to the effect of 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) on topoisomerase II in vitro, the mechanism of DNA breakage induced by ellipticines is most likely due to the drug stabilization of a cleavable complex formed between topoisomerase II and DNA. Protein denaturant treatment of the cleavable complex results in DNA breakage and covalent linking of one topoisomerase II subunit to each 5'-end of the cleaved DNA. Cleavage sites on pBR322 DNA produced by ellipticine or 2-Me-9-OH-E+ treatment mapped at the same positions. However, many of these cleavage sites are distinctly different from those produced by the antitumor drug m-AMSA which also targets at topoisomerase II. Our results thus suggest that although mammalian DNA topoisomerase II may be a common target of these antitumor drugs, drug-DNA-topoisomerase interactions for different antitumor drugs may be different.
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“Anthracyclines are among the most widely used antitumor antibiotics in the clinic and exert antitumor activity mainly by inhibiting topoisomerase II [215,216,217,218,219].”
From Marine Natural Products: A Source of Novel Anticancer Drugs (2019) · cites this paper as [215]
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Cited by
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“Inhibition of Top2 catalytic activity without trapping cleavage complexes is also observed for DNA intercalators at drug concentrations that alter DNA structure, thereby preventing Top2 from binding DNA (step 1 in Figure 5A) or from forming Top2cc (step 3) (Pommier et al., 1984; Tewey et al., 1984).”
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Self-citation
Metadata
- Authors
- Tewey, K. M., Chen, G. L., Nelson, E. M., & Liu, L. F.
- Affiliations
- Johns Hopkins University (US)
- ORCID
- Liu, L F
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1984-07
- Volume
- 259
- Issue
- 14
- Pages
- 9182-9187
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1514525963
- Cited by
- 887
- References
- 39
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 4 · 2023: 4 · 2022: 6 · 2021: 9 · 2020: 10 · 2019: 16 · 2018: 9 · 2017: 15 · 2016: 19 · 2015: 14 · 2014: 14 · 2013: 16 · 2012: 14
- FWCI
- 15.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
- Keywords
- topoisomerase II, epipodophyllotoxins, etoposide, doxorubicin, cleavable complex, drug-enzyme interaction, nalidixic acid, DNA gyrase, cytotoxicity mechanism
- MeSH terms
- Alkaloids, Animals, Antineoplastic Agents, Cattle, DNA, DNA Topoisomerases, Type II, DNA Topoisomerases, Type I, DNA, Viral, Ellipticines, HeLa Cells, Humans, Intercalating Agents, Kinetics, Osmolar Concentration, Plasmids, Protein Binding, Thymus Gland
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