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Cancer Chemotherapy and Pharmacology

, Volume 34, Issue 5, pp 411–415 | Cite as

Synergistic effect of inhibitors of topoisomerase I and II on chromosome damage and cell killing in cultured Chinese hamster ovary cells

  • Felipe Cortés
  • Joaquín Piñero
Original Articles Topoisomerase Inhibitors, Chromosome Damage, Sister Chromatid exchanges, Synergism

Abstract

Simultaneous treatment of cultured Chinese hamster ovary cells with the topoisomerase I inhibitor camptothecin and the topoisomerase II inhibitor 4′-(9-acridinylamino)-methanesulfon-m-anisidide results in a clear synergistic effect on both chromosome damage detected at metaphase and loss of colony-forming ability. In contrast, the effect of combined treatment with these topoisomerase inhibitors on sister chromatid exchanges was not significantly different from that expected if the effects were additive. Taken as a whole, these results seem to support the hypothesis that topoisomerase inhibitors can lead to cell death, presumably when DNA replication forks collide with drug-stabilized cleavable complexes. Nevertheless, no evidence of apoptosis was obtained from DNA fragmentation analysis. The possible clinical implications of our findings are discussed.

Key words

Topoisomerase inhibitors Chromosome damage Sister chromatid exchanges Synergism 

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References

  1. 1.
    Bertrand R, Kerrigan D, Sarang M, Pommier Y (1991) Cell death induced by topoisomerase inhibitors. Role of calcium in mammalian cells. Biochem Pharmacol 42: 77–85Google Scholar
  2. 2.
    Boothman DA, Trask DK, Pardee AB (1987) Inhibition of potentially lethal damage repair in human cells by β-lapachone, an activator of topoisomerase I. Cancer Res 49: 605–612Google Scholar
  3. 3.
    Cortés F, Morgan WF, Wolff S (1987) Effect of exogenous thymidine on sister-chromatid exchange frequency in Chinese hamster ovary cells with bromodeoxyuridine- and chlorodeoxyuridine-substituted chromosomes. Mutat Res 192: 277–282Google Scholar
  4. 4.
    Cortés F, Panneerselvam N, Mateos S, Ortiz T (1993) Poly-d-lysine enhances the genotoxicity of bleomycin in cultured CHO cells. Carcinogenesis 14: 2543–2546Google Scholar
  5. 5.
    Cortés F, Piñero J, Palitti F (1993) Cytogenetic effects of inhibition of topoisomerase I or II activities in the CHO mutant EM9 and its parental line AA8. Mutat Res 288: 281–289Google Scholar
  6. 6.
    Cortés F, Piñero J, Ortiz T (1993) Importance of replication fork progression for the induction of chromosome damage and SCE by inhibitors of DNA topoisomerases. Mutat Res 303: 71–76Google Scholar
  7. 7.
    D'Arpa P, Beardmore C, Liu LF (1990) Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons. Cancer Res 51: 6919–6924Google Scholar
  8. 8.
    Del Bino G, Bruni S, Yi PN, Darzynkiewicz Z (1992) Apoptotic cell cycle specificity and effects of ionizing radiation. Cell Prolif 25: 537–548Google Scholar
  9. 9.
    Dewey WC, Furman SC, Miller HH (1970) Comparison of lethality and chromosome damage induced by X-rays in synchronized Chinese hamster cells in vitro. Radiat Res 43: 561–581Google Scholar
  10. 10.
    Dillehay LE, Denstman SC, Williams JR (1987) Cell cycle dependence of sister chromatid exchange induction by DNA topoisomerase II inhibitors in Chinese hamster V79 cells. Cancer Res 47: 206–209Google Scholar
  11. 11.
    Gallo RC, Whang-Peng J, Adamson RH (1971) Studies on the antitumor activity, mechanism of action, and the cell cycle effects of camptothecin. J Natl Cancer Inst 46: 789–795Google Scholar
  12. 12.
    Giovanella BC, Stehlin JS, Wall ME, Wani MC, Nichola AW, Liu LF, Silber R, Potmesil M (1989) DNA topoisomerase I-targeted chemotherapy of human colon cancer in xenografts. Science 246: 1046–1048Google Scholar
  13. 13.
    Gorczyca W, Bruno S, Darzynkiewicz RJ, Gong J, Darzynkiewicz Z (1992) DNA strand breaks occurring during apoptosis: their early in situ detection by the terminal deoxynucleotidyl transferase and nick translation assays and prevention by serine protease inhibitors. Int J Oncol 1: 639–648Google Scholar
  14. 14.
    Gorczyca W, Gong J, Darzynkiewicz Z (1993) Detection of DNA strand breaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick translation assays. Cancer Res 53: 1945–1951Google Scholar
  15. 15.
    Hickman JA (1992) Apoptosis induced by anticancer drugs. Cancer Metastasis Rev 11: 121–139Google Scholar
  16. 16.
    Holm C, Covey JM, Kerrigan D, Pommier Y (1989) Differential requirement of DNA replication for the cytotoxicity of DNA topoisomerase I and II inhibitors in Chinese hamster DC3F cells. Cancer Res 49: 6365–6368Google Scholar
  17. 17.
    Horwitz MS, Horwitz SB (1971) Intracellular degradation of HeLa and adenovirus type 2 DNA induced by camptothecin. Biochem Biophys Res Commun 45: 723–727Google Scholar
  18. 18.
    Hsiang Y-H, Lihou MG, Liu LF (1989) Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 49: 5077–5082Google Scholar
  19. 19.
    Jaxel C, Taudou G, Portemer C, Mirambeau G, Panijel J, Duguet M (1988) Topoisomerase inhibitors induced irreversible fragmentation of replicated DNA in concanavalin A stimulated splenocytes. Biochemistry 27: 95–99Google Scholar
  20. 20.
    Joshi GP, Nelson WJ, Revell SH, Shaw CA (1982) X-ray induced chromosome damage in live mammalian cells and improved measurements of its effects on their colony forming ability. Int J Radiat Biol 41: 161–181Google Scholar
  21. 21.
    Kalwinsky DK, Look AT, Ducore J, Fridland A (1983) Effects of the epipodophyllotoxin VP16-213 on cell cycle traverse, DNA synthesis, and DNA strand size in cultures of human leukemic lymphoblasts. Cancer Res 43: 1592–1597Google Scholar
  22. 22.
    Kaufmann SH (1989) Induction of endonucleolytic cleavage in human acute myelogenous leukemia cells by etoposide, camptothecin, and other cytotoxic anticancer drugs: a cautionary note. Cancer Res 49: 5870–5878Google Scholar
  23. 23.
    Kaufmann SH (1991) Antagonism between camptothecin and topoisomerase II-directed chemotherapeutic agents in a human leukemia cell line. Cancer Res 51: 1129–1136Google Scholar
  24. 24.
    Kihlman BA, Andersson HC (1985) Synergistic enhancement of the frequency of chromatid aberrations in cultured human lymphocytes by combinations of inhibitors of DNA repair. Mutat Res 150: 313–325Google Scholar
  25. 25.
    Liu LH (1989) DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem 58: 351–375Google Scholar
  26. 26.
    Mattern MR, Hofmann GA, McCabe FL, Jhonson RK (1991) Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor topotecan (SK&F 104864). Cancer Res 51: 5813–5816Google Scholar
  27. 27.
    Moertel CG, Schutt AJ, Reitmeier RJ, Hahn RG (1972) Phase II study of camptothecin (NSC-100880) in the treatment of advanced gastrointestinal cancer. Cancer Chemother Rep 56: 95–101Google Scholar
  28. 28.
    Palitti F, Cortés F, Bassi L, DiChiara D, Fiore M, Piñero J (1993) Higher G2 sensitivity in the CHO mutant EM9 than in its parental line AA8 to the induction of chromosomal damage by camptothecin, an inhibitor of DNA topoisomerase I. Mutat Res 285: 281–285Google Scholar
  29. 29.
    Pinkel D, Thompson LH, Gray JN, Vanderlaan M (1985) Measurement of sister chromatid exchanges at very low bromodeoxyuridine substitution levels using a monoclonal antibody in Chinese hamster ovary cells. Cancer Res 45: 5795–5798Google Scholar
  30. 30.
    Pommier Y (1993) DNA topoisomerase I and II in cancer chemotherapy: update and perspectives. Cancer Chemother Pharmacol 32: 103–108Google Scholar
  31. 31.
    Slichenmayer WJ, Hoff DD von (1990) New natural products in cancer chemotherapy. J Clin Pharmacol 30: 770–788Google Scholar
  32. 32.
    Taudou G, Portemer C, Jaxel C, Duguet M (1993) Inhibition of DNA synthesis and DNA fragmentation in stimulated splenocytes by the concerted action of topoisomerase I and II poisons. Biochem Pharmacol 45: 331–337Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Felipe Cortés
    • 1
  • Joaquín Piñero
    • 1
  1. 1.Department of Cell BiologyFaculty of BiologySevilleSpain

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