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Topoisomerase II-mediated DNA cleavage by amonafide and its structural analogs.
- Source :
-
Molecular pharmacology [Mol Pharmacol] 1989 Sep; Vol. 36 (3), pp. 371-6. - Publication Year :
- 1989
-
Abstract
- Treatment of SV40-infected monkey cells with amonafide (benzisoquinolinedione), an intercalative antitumor drug, resulted in rapid accumulation of linearized intracellular SV40 DNA molecules that were protein linked. Studies using purified mammalian DNA topoisomerase II have shown that amonafide and its structural analogs interfere with the breakage-rejoining reaction of the enzyme by stabilizing a reversible enzyme-DNA "cleavable complex." Denaturation of the cleavable complex with sodium dodecyl sulfate resulted in DNA cleavage and the covalent association of topoisomerase II polypeptides with the cleaved DNA. Unwinding measurements indicate that amonafide is a DNA intercalator. These results suggest that amonafide and its structural analogs (e.g., mitonafide) represent a new class of intercalative topoisomerase II-active antitumor drugs. Different from other topoisomerase II-active antitumor drugs, amonafide and mitonafide induce specific DNA cleavage at a single major site on pBR322 DNA. The strong site specificity of amonafide may allow detailed characterization of the intercalator-stabilized, topoisomerase II-DNA cleavable complex.
- Subjects :
- Adenine
Animals
Cell Line
DNA Topoisomerases, Type II metabolism
DNA, Viral ultrastructure
Haplorhini
In Vitro Techniques
Naphthalimides
Nucleic Acid Conformation
Organophosphonates
Simian virus 40
Structure-Activity Relationship
DNA Damage
DNA, Viral metabolism
Imides
Intercalating Agents
Isoquinolines pharmacology
Topoisomerase II Inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0026-895X
- Volume :
- 36
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 2550774