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Topoisomerases as Novel Targets for Cancer Chemotherapy

Bio/Technology volume 6, pages 1315–1319 (1988)Cite this article

Abstract

Topoisomerase II has been identified as the primary cellular target for a number of antitumor drugs currently being used in cancer chemotherapy. Topoisomerase I has also been found to be the target of camptothecin, an antitumor drug currently under development. Topoisomerases normally solve the topological problems of DN A, which are generated during replication, transcription and recombination, by breaking and rejoining the DNA strands. Topoisomerase-active antitumor drugs interfere with the breakage and rejoining reaction of topoisomerases by trapping an abortive enzyme-DNA “cleavable complex”. The formation of drug-induced “cleavable complexes” effectively converts the enzyme into a cellular poison. The high cellular level of topoisomerase II in some tumors may partly explain the high therapeutic index of these antitumor drugs. Studies of this type of DNA lesion are likely to provide important new information concerning the mechanism of cell killing by antitumor drugs.

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References

  1. Wang, J.C. 1985. DNA Topoisomerases. Ann. Rev. Biochem. 54:665–697.

    Article  CAS  PubMed  Google Scholar 

  2. Wang, J.C. 1987. Recent studies of DNA topoisomerases. Biochim. Biophys. Acta. 909:1–9.

    Article  CAS  PubMed  Google Scholar 

  3. Liu, L.F. 1983. DNA topoisomerases—enzymes that catalyze the breaking and rejoining of DNA. CRC Critical Rev. of Biochem. 15:1–24.

    Article  CAS  Google Scholar 

  4. Yang, L., Wold, M.S., Li, J.J., Kelly, T.J., and Liu, L.F. 1987. Roles of DNA topoisomerases in simian virus 40 DNA replication in vitro. Proc. Natl. Acad. Sci. U.S.A. 84:950–954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Snapka, R.M. 1987. Topoisomerase inhibitors can selectively interfere with different stages of simian virus 40 DNA replication. N.C.I. Monogr. First conference on DNA topoisomerases in cancer chemotherapy. 4:55–60.

    Google Scholar 

  6. DiNardo, S., Voekel, K., and Sternglanz, R. 1984. DNA topoisomerase II mutant of Saccharomyces cerevisiae: Topoisomerase is required for separation of daughter molecules at the termination of DNA replication. Proc. Natl. Acad. Sci. U.S.A. 81:2616–2620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Holm, C., Goto, T., Wang, J.C., and Botstein, D. 1985. DNA topoisomerase II is required at the time of mitosis in yeast. Cell 41:553–563.

    Article  CAS  PubMed  Google Scholar 

  8. Uemura, Y., and Yanagida, M. 1986. Mitotic spindle pulls but fails to separate chromosomes in type II DNA topoisomerase mutants:uncoordinated mitosis. EMBO J. 5:1003–1010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang, H., Wang, J.C., and Liu, L.F. 1988. Involvement of DNA topoisomerase I in transcription of human ribosomal RNA genes. Proc. Natl. Acad. Sci. U.S.A. 85:1060–1064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gilmour, D.S., and Elgin, S.C. 1987. Localization of specific topoisomerase I interactions within the transcribed regions of active heat shock genes by using the inhibitor camptothecin. Mol. Cell. Biol. 7:141–148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rowe, T.C., Couto, E., and Kroll, D.J. 1987. Camptothecin inhibits hsp 70 heat-shock transcription and induces DNA strand breaks in hsp 70 genes in Drosophila. N.C.I. Monogr. First Conference on DNA. Topoisomerases in Cancer Chemotherapy. 4:49–53.

    Google Scholar 

  12. Liu, L.F., and Wang, J.C. 1988. Supercoiling of the DNA template during transcription. Proc. Natl. Acad. Sci. U.S.A. 84:7024–7027.

    Article  Google Scholar 

  13. Wu, H.-Y., Shyy, S., Wang, J.C., and Liu, L.F. 1988. Transcription generates positively and negatively supercoiled domains in the template. Cell 53:433–440.

    Article  CAS  PubMed  Google Scholar 

  14. Liu, L.F., Rowe, T.C., Yang, L., Tewey, K.M., and Chen, G.L. 1983. Cleavage of DNA by mammalian DNA topoisomerase II. J. Biol. Chem. 258:15365–15370.

    CAS  PubMed  Google Scholar 

  15. Champoux, J.J. 1977. Strand breakage by the DNA untwisting enzyme results in covalent attachment of the enzyme to the DNA. Proc. Natl. Acad. Sci. U.S.A. 74:3800–3804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Champoux, J.J. 1981. DNA is linked to the rat liver nicking-closing enzyme by a phosphodiester bond to tyrosine. J. Biol. Chem. 256:4805–4809.

    CAS  PubMed  Google Scholar 

  17. Rowe, T.C., Chen, G.L., Hsiang, Y.-H., and Liu, L.F. 1986. DNA damage by antitumor acridines mediated by mammalian topoisomerase II. Cane. Res. 46:2021–2026.

    CAS  Google Scholar 

  18. Nelson, E.M., Tewey, K.M., and Liu, L.F. 1984. Mechanism of antitumor drug action:poisoning of mammalian DNA topoisomerase II on DNA by 4′-(9-acridinylamino)-methanesulfon-m-anisidide. Proc. Natl. Acad. Sci. U.S.A. 81:1361–1365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kessel, D., Bosmann, H.B., and Lohr, K. 1972. Camptothecin effects on DNA synthesis in murine leukemia cells. Biochim. Biophys. Acta 269:210–216.

    Article  CAS  PubMed  Google Scholar 

  20. Horwitz, M.S., and Horwitz, S.B. 1971. Intracellular degradation of HeLa and Adenovirus type 2 DNA induced by camptothecin. Biochem. Biophys. Res. Commun. 45:723–727.

    Article  CAS  PubMed  Google Scholar 

  21. Loike, J.D., and Horwitz, S.B. 1976. Effect of VP-16-213 on the intracellular degradation of DNA in HeLa cells. Biochem. 15:5443–5448.

    Article  CAS  Google Scholar 

  22. Burr Furlong, N., Sato, J., Brown, T., Chavez, F., and Hurlbert, R.B. 1978. Induction of limited DNA damage by the antitumor agent Cain's acridine. Cancer Res. 38:1329–1335.

    Google Scholar 

  23. Robertson, I.G.C., Denny, W.A., and Baguley, B.C. 1980. Inhibition of T4 bacteriophage yield by 9-anilinoacridines; comparison with in vivo antitumor activity. Eur. J. Cancer 16:1133–1139.

    Article  CAS  PubMed  Google Scholar 

  24. Baguley, B.C., and Nash, R. 1981. Antitumor activity of substituted 9-anilinoacridines—comparison of in vivo and in vitro testing systems. Eur. J. Cancer 17:671–679.

    Article  CAS  PubMed  Google Scholar 

  25. Ross, W.E., Glaubinger, D.L., and Kohn, K.W. 1979. Qualitative and quantitative aspects of intercalator-induced DNA strand breaks. Biochim. Biophys. Acta 562:41–50.

    Article  CAS  PubMed  Google Scholar 

  26. Marshall, B., Ralph, R.K., and Hancock, R. 1983. Blocked 5′-termini in the fragments of chromosomal DNA produced in cells exposed to the antitumor drug 4′-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA). Nucl. Acids Res. 11:4251–4256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ralph, R.K., and Hancock, R. 1985. Chromosomal DNA fragment from mouse cells exposed to an intercalating agent containing a 175-kdalton terminal polypeptide. Can. J. Biochem. Cell. Biol. 63:780–783.

    Article  CAS  PubMed  Google Scholar 

  28. Zwelling, L.A., Michaels, S., Erickson, L.C., Ungerleider, R.S., Nichols, M., and Kohn, K.W. 1981. Protein-associated deoxyribonu-cleic acid strand breaks in L1210 cells treated with deoxyribonucleic acid intercalating agents 4′-(9-acridinylamino)methanesulfon-m-anisidide and adriamycin. Biochem. 20:6553–6563.

    Article  CAS  Google Scholar 

  29. Ross, W.E., Glaubinger, D.L., and Kohn, K.W. 1978. Protein-associated DNA breaks in cells treated with adriamycin or ellipticine. Biochim. Biophys. Acta 519:23–30.

    Article  CAS  PubMed  Google Scholar 

  30. Filipski, J., and Kohn, K.W. 1982. Ellipticine-induced protein-associated DNA breaks in isolated L1210 nuclei. Biochim. Biophys. Acta 698:280–286.

    Article  CAS  PubMed  Google Scholar 

  31. Ross, W.E., Zwelling, L.A., and Kohn, L.W. 1979. Relationship between cytotoxicity and DNA strand breakage produced by adriamycin and other intercalating agents. Int. J. Radiat. Oncol. Biol. Phys. 5:1221–1225.

    Article  CAS  PubMed  Google Scholar 

  32. Tewey, K.M., Rowe, T.C., Yang, L., Halligan, B.D., and Liu, L.F. 1984. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 226:466–468.

    Article  CAS  PubMed  Google Scholar 

  33. Tewey, K.M., Chen, G.L., Nelson, E.M., and Liu, L.F. 1984. Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J. Biol. Chem. 259:9182–9187.

    CAS  PubMed  Google Scholar 

  34. Chen, G.L., Yang, L., Rowe, T.C., Halligan, B.D., Tewey, K.M., and Liu, L.F. 1984. Nonintercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J. Biol. Chem. 259:13560–13566.

    CAS  PubMed  Google Scholar 

  35. Ross, W.E., Rowe, T.C., Glisson, B., Yalowich, J., and Liu, L.F. 1984. Role of topoisomerase II in mediating epipodophyllotoxin induced DNA cleavage. Cancer Res. 44:5857–5860.

    CAS  PubMed  Google Scholar 

  36. Yang, L., Rowe, T.C., Nelson, E.M., and Liu, L.F. 1985. In vivo mapping of DNA topoisomerase II specific cleavage sites on SV40 chromatin. Cell 41:127–132.

    Article  CAS  PubMed  Google Scholar 

  37. Yang, L., Rowe, T.C., and Liu, L.F. 1985. Identification of DNA topoisomerase II as an intracellular target of antitumor epipodophyl-lotoxins in SV40 infected monkey cells. Cancer Res. 45:5872–5876.

    CAS  PubMed  Google Scholar 

  38. Rowe, T.C., Chen, G.L., Hsiang, Y.-H., and Liu, L.F. 1986. DNA damage by antitumor acridities mediated by mammalian DNA topoisomerase II. Cancer Res. 46:2021–2026.

    CAS  PubMed  Google Scholar 

  39. Long, B.H. 1987. Structure-activity relationships of podophyllotoxin congeners that inhibit topoisomerase II. N.C.I. Monogr. First Conference on DNA Topoisomerases in Cancer Chemotherapy. 4:123–127.

    Google Scholar 

  40. Rowe, T.C., Kupfer, G., and Ross, W.E. 1985. Inhibition of epipodophyllotoxin cytotoxicity by interference with topoisomerase-mediated DNA cleavage. Biochem. Pharm. 34:2483–2487.

    Article  CAS  PubMed  Google Scholar 

  41. Glisson, B., Gupta, R., Smallwood-Kentro, S., and Ross, W. 1986. Characterization of acquired epipodophyllotoxin resistance in a Chinese hamster ovary cell line: loss of drug-stimulated DNA cleavage activity. Cancer Res. 46:1934–1938.

    CAS  PubMed  Google Scholar 

  42. Glisson, B., Gupta, R., Hodges, P., and Ross, W. 1986. Cross-resistance to intercalating agents in an epipodophyllotoxin-resistant Chinese hamster ovary cell line: evidence for a common intracellular target. Cancer Res. 46:1939–1942.

    CAS  PubMed  Google Scholar 

  43. Bodley, A.L., Liu, L.F., Israel, M., Giuliani, F.C., Silber, R., Kirs-chenbaum, S., and Potmesil, M. 1988. DNA Topoisomerase II mediated of doxorubicin and daunomycin congeners with DNA. Cancer Res. manuscript submitted.

  44. Kupfer, G., Bodley, A.L., and Liu, L.F. 1987. Involvement of intracellular ATP in cytotoxicity of topoisomerase-targeting antitumor drugs. N.C.I. Monogr. First Conference on DNA Topoisomerases in Cancer Chemotherapy. 4:37–40.

    Google Scholar 

  45. Drlica, K. 1984. Biology of bacterial deoxyribonucleic acid topoisomerases. Microbiol. Rev. 48:273–289.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Pedrini, A.M. 1979. Nalidixic acid. Antibiotics (NY) 5:154–175.

    CAS  Google Scholar 

  47. Chen, G.L., and Liu, L.F. 1986. DNA topoisomerases as therapeutic targets in cancer chemotherapy. Ann. Reports Med. Chem. 21:257–262.

    Article  CAS  Google Scholar 

  48. Bodley, A.L., and Liu, L.F. 1988. Roles of DNA topoisomerases in drug cytotoxicity and drug resistance. Bristol-Myers Cancer Symposia: Mechanisms of Drug Resistance in Neoplastic Cells 9:277–286.

  49. Dillehay, L.E., Denstman, S.C., and Williams, J.R. 1987. Cell cycle dependence of sister chromotid exchange induction by DNA topoisomerase II inhibitors in Chinese hamster V79 cells. Cancer Res. 47:206–209.

    CAS  PubMed  Google Scholar 

  50. Deaven, L.L., Oka, M.S., and Tobey, R.A. 1978. Cell-cycle-specific chromosome damage following treatment of cultured Chinese hamster cells with 4′-(9-acridinylamino)methanesulfon-m-anisidide-HCl. J. Natl. Cancer Inst. 60:1155–1161.

    Article  CAS  PubMed  Google Scholar 

  51. DeMarini, D.M., Doerr, C.L., Meyer, M.K., Brock, K.H., Hozier, J., and Moore, M.M. 1987. Mutagenicity of m-AMSA and o-AMSA in mammalian cells due to clastogenic mechanism:possible role of topoisomerase. Mutagenesis 2:349–355.

    Article  CAS  PubMed  Google Scholar 

  52. Scher, W., and Friend, C. 1978. Breakage of DNA and alterations in folded genomes by inducers of differentiation in murine erythroleukemia cells. Cancer Res. 38:841–849.

    CAS  PubMed  Google Scholar 

  53. Walker, G.C. 1984. Mutagenesis and inducible responses to deoxyribonucleic acid damage in Eschericia coli. Microbiol. Rev. 48:60–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Walker, G.C., Marsh, L., and Dodson, L.A. 1985. Genetic analysis of DNA repair: inference and extrapolation. Ann. Rev. Genet. 19:103–126.

    Article  CAS  PubMed  Google Scholar 

  55. Nitiss, J., and Wang, J.C. 1988. Actions of DNA topoisomerase-targeting antitumor drugs can be studied in yeast mutants. Proc. Natl. Acad. Sci. U.S.A. in press.

  56. Nelson, W.G., Cho, K.R., Hsiang, Y.-H., Liu, L.F., and Coffey, D.S. 1987. Growth related elevations of topoisomerase II levels found in Dunning R3327 rat prostatic adenocarcinomas. Cancer Res. 47:3246–3250.

    CAS  PubMed  Google Scholar 

  57. Hsiang, Y.-H., Wu, H.-Y., and Liu, L.F. 1988. Proliferation-dependent regulation of DNA topoisomerase II in cultured human cells. Cancer Res. 48:3230–3235.

    CAS  PubMed  Google Scholar 

  58. Baguley, B.C., and Cain, B.F. 1982. Comparison of the in vivo and in vitro antileukemic activity of monosubstituted derivatives of 4′-(9-acridinylamino)methanesulfon-m-anisidide. Molecular Pharm. 22:486–492.

    CAS  Google Scholar 

  59. Potmesil, M., Hsiang, Y.-H., Liu, L.F., Wu, H.-Y., Traganos, F., Bank, B., and Silber, R. 1987. DNA topoisomerae II as a potential factor in drug resistance of human malignancies. N.C.I. Monogr. First Conference on DNA Topoisomerases in Cancer Chemotherapy 4:105–109.

    Google Scholar 

  60. Spadari, S., Pedrali-Noy, G., Focher, F., Montecucco, A., Bordoni, T., Geroni, C., Giuliani, F.C., Ventrella, G., Arcamone, F., and Ciarroc-chi, G. 1986. DNA polymerases and DNA topoisomerases as targets for the development of anticancer drugs. Anticancer Res. 6:935–940.

    CAS  PubMed  Google Scholar 

  61. Abelson, H.T., and Penman, S. 1972. Selective interruption of high molecular weight RNA synthesis in HeLa cells by camptothecin. Nature 237:144–146.

    CAS  Google Scholar 

  62. Hsiang, Y.-H., Hertzberg, R., Hecht, S., and Liu, L.F. 1985. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J. Biol. Chem. 260:14873–14878.

    CAS  PubMed  Google Scholar 

  63. Mattern, M.R., Mong, S.-M., Bartus, H.F., Mirabelli, C.K., Crooke, S.T., and Johnson, R.K. 1987. Relationship between the intracellular effects of camptothecin and the inhibition of DNA topoisomerase I in cultured L1210 cells. Cancer Res. 47:7193–7198.

    Google Scholar 

  64. Andoh, T., Ishii, K., Suzuki, Y., Ikegami, Y., Kusunoki, Y., Takemoto, Y., and Okada, K. 1987. Characterization of a mammalian mutant with a camptothecin-resistant DNA topoisomerase I. Proc. Natl. Acad. Sci. U.S.A. 84:5565–5569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kjeldson, E., Bonven, B.J., Andoh, T., Ishii, K., Okada, K., Bolund, L., and Westergaard, O. 1988. Characterization of a camptothecin-resistant human DNA topoisomerase I. J. Biol. Chem. 263:3912–3916.

    Google Scholar 

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  1. Department of Biological Chemistry, Johns Hopkins School of Medicine, 725 N. Wolfe Street, Baltimore, Maryland, 21205

    Annette L. Bodley & Leroy F. Liu

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Bodley, A., Liu, L. Topoisomerases as Novel Targets for Cancer Chemotherapy. Nat Biotechnol 6, 1315–1319 (1988). https://doi.org/10.1038/nbt1188-1315

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