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Doxorubicin inhibits human DNA topoisomerase I

  • Original Articles
  • Doxorubicin, DNA topoisomerase I, Antitumor drug
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Summary

Purified human DNA topoisomerase I was assayed quantitatively by enzyme titrations with supercoiled pHC624 DNA in the presence of 0–2.0 μm doxorubicin. Supercoiled and relaxed DNAs were resolved by agarose gel electrophoresis in the presence of ethidium bromide, and the pereentage of conversion of supercoiled DNA to relaxed DNA was quantified by scanning microdensitometry. The inhibition of DNA topoisomerase I activity was measured at varying concentrations of doxorubicin. Doxorubicin inhibited enzyme activity at an IC50 value (the concentration required to inhibit 50% of the total activity) of 0.8 μm. Similar inhibition was observed for daunomycin, a structurally related anthracycline antitumor drug. These results indicate that anthracyclines inhibit human DNA topoisomerase I activity at concentrations that cause DNA damage and cytotoxicity in vivo.

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References

  1. Bjornsti M-A, Benedetti P, Viglianti GA, Wang JC (1989) Expression of human DNA topoisomerase I in yeast cells lacking yeast DNA topoisomerase I: restoration of sensitivity of the cells to the antitumor drug camptothecin. Cancer Res 49:6318

    Google Scholar 

  2. Castora FJ, Kelly WG (1986) ATP inhibits nuclear and mitochondrial type I topoisomerases from human leukemia cells. Proc Natl Acad Sci USA 83:1680

    Google Scholar 

  3. Cole SPC, Chanda ER, Dicke FP, Gerlach JH, Mirski SE (1991) Non-P-glycoprotein-mediated multidrug resistance in a small-cell lung cancer cell line: evidence for decreased susceptibility to drug-induced DNA damage and reduced levels of topoisomerase II. Cancer Res 51:3345

    Google Scholar 

  4. Davis LG, Dibner MD, Battey JF (1986) Plasmid DNA preparation: triton-lysozyme method: In: Basic methods in molecular biology. Elsevier, Amsterdam, p 93

    Google Scholar 

  5. Deffie AM, Batra JK, Goldenberg GJ (1989) Direct correlation between DNA topoisomerase II activity and cytotoxicity in Adriamycinsensitive and-resistant P388 leukemia cell lines. Cancer Res 49:58

    Google Scholar 

  6. Fairfield FR, Bauer WR, Simpson MV (1979) Mitochondria contain a distinct DNA topoisomerase. J Biol Chem 254:9352

    Google Scholar 

  7. Foglesong PD, Bauer WR (1984) Effects of ATP and inhibitory factors on the activity of vaccinia virus type I topoisomerase. J Virol 49:1

    Google Scholar 

  8. Gupta RS, Gupta R, Eng B, Lock RB, Ross WE, Hertzberg RP, Caranfa MJ, Johnson RK (1988) Camptothecin-resistant mutants of Chinese hamster ovary cells containing a resistant form of topoisomerase I. Cancer Res 48:6404

    Google Scholar 

  9. Horio M, Gottesman MM, Pastan I (1988) ATP-dependent transport of vinblastine in vesicles from human multidrug-resistant cells. Proc Natl Acad Sci USA 85:3580

    Google Scholar 

  10. Hsiang Y-H, Hertzberg R, Hecht S, Liu LF (1985) Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 260:14873

    Google Scholar 

  11. Jong S de, Zijlstra JG, Vries EGE de, Mulder NH (1990) Reduced DNA topoisomerase II activity and drug-induced DNA cleavage activity in an Adriamycin-resistant human small-cell lung carcinoma cell line. Cancer Res 50:304

    Google Scholar 

  12. Liu LF (1989) DNA topoisomerases poisons as antitumor drugs. Annu Rev Biochem 58:351

    Google Scholar 

  13. Maxwell A, Gellert M (1986) Mechanistic aspects of DNA topoisomerases. In: Anfinsen CB, Epsall JT, Richards FM (eds) Advances inprotein chemistry, vol 38. Academic Press, San Diego, p69

    Google Scholar 

  14. Pommier Y, Kerrigan D, Schwartz RE, Swack JA, McCurdy A (1986) Altered DNA topoisomerase II activity in Chinese hamster cells resistant to topoisomerase II inhibitors. Cancer Res 46:3075

    Google Scholar 

  15. Shaffer R, Traktman P (1987) Vaccinia virus encapsulates a novel topoisomerase with the properties of a eucaryotic type I enzyme. J Biol Chem 262:9309

    Google Scholar 

  16. Sugimoto Y, Tsukahara S, Oh-Hara T, Isoe T, Tsuruo T (1990) Decreased expression of DNA topoisomerase I in camptothecin-resistant tumor cell lines as determined by a monoclonal antibody. Cancer Res 50:6925

    Google Scholar 

  17. Tewey KM, Rowe TC, Yang L, Halligan BD, Liu LF (1984) Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 226:466

    Google Scholar 

  18. Vosberg H-P (1986) DNA topoisomerases: enzymes that control DNA conformation: In: Cooper M, Eisen H, Goebel W, Hofschneider PH, Koprowski H, Melchers F, Oldstone M, Rott R, Schweiger HG, Vogt PK, Wilson I (eds) Currenttopics in microbiology and immunology, vol 114. Springer, Berlin Heidelberg New York, p 19

    Google Scholar 

  19. Wang JC (1985) DNA topoisomerases. Annu Rev Biochem 54:665

    Google Scholar 

  20. Wasserman K, Markovits J, Jaxel C, Capranico G, Kohn K, Pommier Y (1990) Effects of morpholinyl doxorubicins, doxorubicin, and actinomycin D on mammalian DNA topoisomerases I and II. Mol Pharmacol 38:38

    Google Scholar 

  21. Zwelling LA, Michaels S, Erikson LC, Ungerleider RS, Nichols M, Kohn KW (1981) 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 20:6553

    Google Scholar 

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Authors and Affiliations

  1. Biology Department, Rutgers University, 08 102, Camden, New Jersey, USA

    P. David Foglesong, Calvin Reckord & Sharon Swink

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  1. P. David Foglesong
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  2. Calvin Reckord
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  3. Sharon Swink
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Additional information

This investigation was supported by grants from the Research Council of Rutgers University and the Charles and Johanna Busch Bequest

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David Foglesong, P., Reckord, C. & Swink, S. Doxorubicin inhibits human DNA topoisomerase I. Cancer Chemother. Pharmacol. 30, 123–125 (1992). https://doi.org/10.1007/BF00686403

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  • DOI: https://doi.org/10.1007/BF00686403

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