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. 1988 May 11;16(9):3907–3918. doi: 10.1093/nar/16.9.3907

DNA unwinding and inhibition of T4 DNA ligase by anthracyclines.

A Montecucco 1, G Pedrali-Noy 1, S Spadari 1, E Zanolin 1, G Ciarrocchi 1
PMCID: PMC336564  PMID: 3287337

Abstract

The ability to alter DNA tertiary structure of ten anthracycline derivatives whose antitumor potency is known was studied by an assay that makes use of nicked circular DNA and bacteriophage T4 DNA ligase. This assay allows the detection of tertiary structure alterations caused by DNA binding of both intercalating and non-intercalating drugs. The determination of these events can be obtained at different temperatures in the range of activity of DNA ligase. The results indicate that anthracyclines alter the DNA tertiary structure but this property does not correlate with their cytotoxic or antitumor activities. An additional interesting finding was that several anthracyclines inhibit T4 DNA ligase. The inhibition can be complete and is a cubic function of drug concentration. The inhibition of DNA ligase does not correlate with the ability of anthracyclines to alter the tertiary structure of DNA but is dependent from the presence of an amino group on the sugar ring.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. BOLLUM F. J. Thermal conversion of nonpriming deoxyribonucleic acid to primer. J Biol Chem. 1959 Oct;234:2733–2734. [PubMed] [Google Scholar]
  2. Chen G. L., Yang L., Rowe T. C., Halligan B. D., Tewey K. M., Liu L. F. Nonintercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J Biol Chem. 1984 Nov 10;259(21):13560–13566. [PubMed] [Google Scholar]
  3. Ciarrocchi G., Pedrini A. M. Determination of pyrimidine dimer unwinding angle by measurement of DNA electrophoretic mobility. J Mol Biol. 1982 Feb 25;155(2):177–183. doi: 10.1016/0022-2836(82)90445-4. [DOI] [PubMed] [Google Scholar]
  4. Ciarrocchi G., Sutherland B. M. Irradiation of circular DNA with 254 nm radiation or sensitization in the presence of Ag+: evidence for unwinding by photoproducts other than pyrimidine dimers. Photochem Photobiol. 1983 Sep;38(3):259–263. doi: 10.1111/j.1751-1097.1983.tb02670.x. [DOI] [PubMed] [Google Scholar]
  5. Ciomei M., Spadari S., Pedrali-Noy G., Ciarrocchi G. Structural alterations of pathologically or physiologically modified DNA. Nucleic Acids Res. 1984 Feb 24;12(4):1977–1989. doi: 10.1093/nar/12.4.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Depew D. E., Wang J. C. Conformational fluctuations of DNA helix. Proc Natl Acad Sci U S A. 1975 Nov;72(11):4275–4279. doi: 10.1073/pnas.72.11.4275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Markovits J., Pommier Y., Kerrigan D., Covey J. M., Tilchen E. J., Kohn K. W. Topoisomerase II-mediated DNA breaks and cytotoxicity in relation to cell proliferation and the cell cycle in NIH 3T3 fibroblasts and L1210 leukemia cells. Cancer Res. 1987 Apr 15;47(8):2050–2055. [PubMed] [Google Scholar]
  8. Modrich P., Lehman I. R. Enzymatic joining of polynucleotides. IX. A simple and rapid assay of polynucleotide joining (ligase) activity by measurement of circle formation from linear deoxyadenylate-deoxythymidylate copolymer. J Biol Chem. 1970 Jul 25;245(14):3626–3631. [PubMed] [Google Scholar]
  9. Pedrini A. M., Ciarrocchi G. Inhibition of Micrococcus luteus DNA topoisomerase I by UV photoproducts. Proc Natl Acad Sci U S A. 1983 Apr;80(7):1787–1791. doi: 10.1073/pnas.80.7.1787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Pommier Y., Covey J. M., Kerrigan D., Markovits J., Pham R. DNA unwinding and inhibition of mouse leukemia L1210 DNA topoisomerase I by intercalators. Nucleic Acids Res. 1987 Aug 25;15(16):6713–6731. doi: 10.1093/nar/15.16.6713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Spadari S., Pedrali-Noy G., Focher F., Montecucco A., Bordoni T., Geroni C., Giuliani F. C., Ventrella G., Arcamone F., Ciarrocchi G. DNA polymerases and DNA topoisomerases as targets for the development of anticancer drugs. Anticancer Res. 1986 Sep-Oct;6(5):935–940. [PubMed] [Google Scholar]
  12. Spadari S., Sutherland B. M., Pedrali-Noy G., Focher F., Chiesa M. T., Ciarrocchi G. Alteration of DNA tertiary structure by physical and chemical carcinogens: involvement in DNA repair processes. Toxicol Pathol. 1987;15(1):82–87. doi: 10.1177/019262338701500111. [DOI] [PubMed] [Google Scholar]
  13. Tewey K. M., Rowe T. C., Yang L., Halligan B. D., Liu L. F. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science. 1984 Oct 26;226(4673):466–468. doi: 10.1126/science.6093249. [DOI] [PubMed] [Google Scholar]
  14. Valentini L., Nicolella V., Vannini E., Menozzi M., Penco S., Arcamone F. Association of anthracycline derivatives with DNA: a fluorescence study. Farmaco Sci. 1985 Jun;40(6):377–390. [PubMed] [Google Scholar]
  15. Wang J. C., Jacobsen J. H., Saucier J. M. Physiochemical studies on interactions between DNA and RNA polymerase. Unwinding of the DNA helix by Escherichia coli RNA polymerase. Nucleic Acids Res. 1977;4(5):1225–1241. doi: 10.1093/nar/4.5.1225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Wang J. C., Peck L. J., Becherer K. DNA supercoiling and its effects on DNA structure and function. Cold Spring Harb Symp Quant Biol. 1983;47(Pt 1):85–91. doi: 10.1101/sqb.1983.047.01.011. [DOI] [PubMed] [Google Scholar]
  17. Wang J. C. The degree of unwinding of the DNA helix by ethidium. I. Titration of twisted PM2 DNA molecules in alkaline cesium chloride density gradients. J Mol Biol. 1974 Nov 15;89(4):783–801. doi: 10.1016/0022-2836(74)90053-9. [DOI] [PubMed] [Google Scholar]
  18. Zwelling L. A., Michaels S., Erickson L. C., Ungerleider R. S., Nichols M., Kohn K. W. Protein-associated deoxyribonucleic acid strand breaks in L1210 cells treated with the deoxyribonucleic acid intercalating agents 4'-(9-acridinylamino) methanesulfon-m-anisidide and adriamycin. Biochemistry. 1981 Nov 10;20(23):6553–6563. doi: 10.1021/bi00526a006. [DOI] [PubMed] [Google Scholar]

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