DNA damage by antitumor acridines mediated by mammalian DNA topoisomerase II.

Antitumor drugs from many chemical classes have been shown to induce protein-linked DNA breaks in cultured mammalian cells and in vitro in the presence of purified mammalian DNA topoisomerase II. The possibility that mammalian DNA topoisomerase II is an intracellular target which mediates drug-induced DNA breaks is supported by the following studies using 4'-(9-acridinylamino)methane-sulfon-m-anisidide (m-AMSA): (a) a single m-AMSA-dependent DNA cleavage activity copurified with calf thymus DNA topoisomerase II activity at all chromatographic steps of the enzyme purification; (b) m-AMSA-induced DNA cleavage by this purified activity resulted in the covalent attachment of protein to the 5'-ends of the DNA via a tyrosyl phosphate bond. This covalently linked protein has the same reduced molecular weight as purified calf thymus DNA topoisomerase II. The possibility that topoisomerase II-mediated DNA breaks may be responsible for cytotoxicity has also been investigated using a number of m-AMSA-related acridines. The level of topoisomerase II-mediated DNA breaks in vitro strongly correlates with the level of protein-linked DNA breaks in cultured cells and drug-induced cytotoxicity. These results suggest that mammalian DNA topoisomerase II may be a cytotoxic target of antitumor acridines.

[1]  L. Liu,et al.  Purification and characterization of a type II DNA topoisomerase from bovine calf thymus. , 1985, The Journal of biological chemistry.

[2]  L. Liu,et al.  Nonintercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. , 1984, The Journal of biological chemistry.

[3]  L. Liu,et al.  Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. , 1984, Science.

[4]  L. Liu,et al.  Identification of the breakage-reunion subunit of T4 DNA topoisomerase. , 1984, The Journal of biological chemistry.

[5]  L. Liu,et al.  Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. , 1984, The Journal of biological chemistry.

[6]  L. Liu,et al.  Cleavage of DNA by mammalian DNA topoisomerase II. , 1983, The Journal of biological chemistry.

[7]  R. Ralph,et al.  Blocked 5'-termini in the fragments of chromosomal DNA produced in cells exposed to the antitumor drug 4'-[(9-acridinyl)-amino]methanesulphon-m-anisidide (mAMSA). , 1983, Nucleic acids research.

[8]  K. Kohn,et al.  Protein-associated deoxyribonucleic acid strand breaks produced in mouse leukemia L1210 cells by ellipticine and 2-methyl-9-hydroxyellipticinium. , 1982, Biochemical pharmacology.

[9]  B. Baguley,et al.  Comparison of the in vivo and in vitro antileukemic activity of monosubstituted derivatives of 4'-(9-acridinylamino)methanesulfon-m-anisidide. , 1982, Molecular pharmacology.

[10]  Y. Pommier,et al.  The formation and resealing of intercalator-induced DNA strand breaks in isolated L1210 cell nuclei. , 1982, Biochemical and biophysical research communications.

[11]  L. Zwelling,et al.  Cytotoxicity and DNA strand breaks by 5-iminodaunorubicin in mouse leukemia L1210 cells: comparison with adriamycin and 4'-(9-acridinylamino)methanesulfon-m-anisidide. , 1982, Cancer research.

[12]  L. Liu,et al.  Intra- and intermolecular strand transfer by HeLa DNA topoisomerase I. , 1982, The Journal of biological chemistry.

[13]  L. Liu,et al.  Novel topologically knotted DNA from bacteriophage P4 capsids: studies with DNA topoisomerases. , 1981, Nucleic acids research.

[14]  W. Ross,et al.  DNA double-stranded breaks in mammalian cells after exposure to intercalating agents. , 1981, Biochimica et biophysica acta.

[15]  N. Cozzarelli.  DNA gyrase and the supercoiling of DNA. , 1980, Science.

[16]  K. Kohn,et al.  Qualitative and quantitative aspects of intercalator-induced DNA strand breaks. , 1979, Biochimica et biophysica acta.

[17]  E. Witkin,et al.  Targeted and untargeted mutagenesis by various inducers of SOS functions in Escherichia coli. , 1979, Cold Spring Harbor symposia on quantitative biology.

[18]  C. Paoletti,et al.  Ellipticine and derivatives induce breakage of L1210 cells DNA in vitro. , 1979, Biochemical pharmacology.

[19]  K W Kohn,et al.  Protein-associated DNA breaks in cells treated with adriamycin or ellipticine. , 1978, Biochimica et biophysica acta.

[20]  T. Brown,et al.  Induction of limited DNA damage by the antitumor agent Cain's acridine. , 1978, Cancer research.

[21]  G. Atwell,et al.  Potential antitumor agents. 12. 9-Anilinoacridines. , 1972, Journal of medicinal chemistry.

[22]  M. Waring,et al.  Variation of the supercoils in closed circular DNA by binding of antibiotics and drugs: evidence for molecular models involving intercalation. , 1970, Journal of molecular biology.

[23]  Nalidixic Acid.  Nalidixic acid , 1970, The Medical letter on drugs and therapeutics.

[24]  T. H. Wood,et al.  Escherichia coli K-12 Mutants Resistant to Nalidixic Acid: Genetic Mapping and Dominance Studies , 1969, Journal of bacteriology.

[25]  W. Goss,et al.  Mechanism of Action of Nalidixic Acid on Escherichia coli III. Conditions Required for Lethality , 1966, Journal of bacteriology.