Skip to main content
SpringerLink
Log in
Book cover

Camptothecins in Cancer Therapy pp 39–59Cite as

Inhibitors of Topoisomerase I Function

  • Chapter

  • 740 Accesses

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

As noted elsewhere in this book, the locus of action of camptothecin (CPT) (1) (Fig. 1) as an antitumor agent involves the noncovalent binding of this agent to the covalent binary complex formed between topoisomerase I (TOP-I) and DNA (Fig. 2) (1). Although the equilibrium between free enzyme and the enzyme-DNA binary complex normally lies far toward free enzyme and DNA, in the presence of CPT, the equilibrium is rapidly displaced toward ternary complex (2). At this level, the action of CPT on TOP-I function is entirely analogous to those of several agents that inhibit the function of topoisomerase II, including 4-(9-acridinylamino)-N-(methanesulfonyl)-m-anisidine (m-AMSA), etoposide, and teniposide (3).

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Hsiang YH, Hertzberg R, Hecht SM, Liu LF. 1985 Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 260:14873–14878.

    Google Scholar 

  2. Hertzberg RP, Caranfa MJ, Hecht SM. 1989 On the mechanism of topoisomerase I inhibition by camptothecin: evidence for binding to an enzyme-DNA complex. Biochemistry 28:4629–4638.

    Google Scholar 

  3. Liu LF. 1989 DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem 58:351–375.

    Google Scholar 

  4. Hsiang Y, Lihour 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 49:5077–5082.

    Google Scholar 

  5. Liu LF. 1990 Anticancer drugs that convert DNA topoisomerases into DNA damaging agents. In: DNA Topology and Its Biological Effects. Cozzarelli NR, Wang JC, eds. Cold Spring Harbor Laboratory, New York, 371–389.

    Google Scholar 

  6. Hertzberg RP, Caranfa MJ, Holden KG, et al. 1989 Modification of the hydroxy lactone ring of camptothecin: inhibition of mammalian topoisomerase I and biological activity. J Med Chem 32:715–720.

    Google Scholar 

  7. Kingsbury WD, Boehm JC, Jakas DR, et al. 1991 Synthesis of water-soluble (aminoalkyl)camptothecin analogues: inhibition of topoisomerase I antitumor activity. J Med Chem 34:98–107.

    Google Scholar 

  8. Wang X, Zhou X, Hecht SM. 1999 Role of the 20-hydroxyl group in camptothecin binding by the topoisomerase I-DNA binary complex. Biochemistry 38:4374–4381.

    Google Scholar 

  9. Liehr JG, Giovanella BC, Verschraegen CF, eds. 2000 The camptothecins. Unfolding their anticancer potential. Vol. 922. Annals New York Academy Sciences, New York.

    Google Scholar 

  10. Wani MC, Ronman PE, Lindley JT, Wall ME. 1980 Plant antitumor agents. 18. Synthesis and biological activity of camptothecin analogues. J Med Chem 23:554–560.

    Google Scholar 

  11. Jaxel C, Kohn KW, Wani MC, Wall ME, Pommier Y. 1989 Structure-activity study of the actions of camptothecin derivatives on mammalian topoisomerase I: evidence for a specific receptor site and a relation to antitumor activity. Cancer Res 49:1465–1469.

    Google Scholar 

  12. Adamovics JA, Hutchinson CR. 1979 Prodrug analogues of the antitumor alkaloid camptothecin. J Med Chem 22:310–314.

    Google Scholar 

  13. Burke TG, Mishra AK, Wani MC, Wall ME. 1993 Lipid bilayer partitioning and stability of camptothecin drugs. Biochemistry 32:5352–5364.

    Google Scholar 

  14. Mi Z, Burke TG. 1994 Differential interactions of camptothecin lactone and carboxylate forms with human blood components. Biochemistry 33:10325–10336.

    Google Scholar 

  15. Mi Z, Malak H, Burke TG. 1995 Reduced albumin binding promotes the stability and activity of topotecan in human blood. Biochemistry 34:13722–13728.

    Google Scholar 

  16. Lavergne O, Demarquay D, Kasprzyk PG, Bigg DCH. 2000 Homocamptothecins E-ring modified CPT analogues. In: The camptothecins. Unfolding their anticancer potential. Vol. 922. Liehr JG, Giovanella BC, Verschraegen CF, eds. Annals New York Academy Sciences, New York, 100–111.

    Google Scholar 

  17. Lavergne O, Lesueur-Ginot L, Pla Rodas F, Bigg DCH. 1997 BN 80245: an E-ring modified camptothecin with potent antiproliferative and topoisomerase I inhibitory activities. Bioorg Med Chem Lett 7:2235–2238.

    Google Scholar 

  18. Lavergne O, Lesueur-Ginot F, Pla Rodas F, et al. 1998 Homocamptothecins: synthesis and antitumor activity of novel E-ring-modified camptothecin analogues. J Med Chem 41:5410–5419.

    Google Scholar 

  19. Nitiss JL, Wang JC. 1988 DNA topoisomerase-targeting antitumor drugs can be studied in yeast. Proc Natl Acad Sci USA 85:7501–7505.

    Google Scholar 

  20. Eng WK, Faucette L, Johnson RK, Sternglanz R. 1988 Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. Mol Pharmacol 34:755–760.

    Google Scholar 

  21. Bjornsti MA, Benedetti P, Viglianti GA. 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 49:6318–6323.

    Google Scholar 

  22. Gupta RS, Gupta R, Eng B, et al. 1988 Camptothecin-resistant mutants of Chinese hamster ovary cells containing a resistant form of topoisomerase I. Cancer Res 48:6404–6410.

    Google Scholar 

  23. Kjeldsen E, Bonven BJ, Andoh T, et al. 1988 Characterization of a camptothecin-resistant human DNA topoisomerase I. J Biol Chem 263:3912–3916.

    Google Scholar 

  24. Wang LK, Johnson RK, Hecht SM. 1993 Inhibition of topoisomerase I function by nitidine and fagaronine. Chem Res Toxicol 6:813–818.

    Google Scholar 

  25. Yamashita Y, Fujii N, Murakata C, Ashizawa T, Okabe M, Nakano H. 1992 Induction of mammalian DNA topoisomerase I mediated DNA cleavage by antitumor indolocarbazole derivatives. Biochemistry 31:12069–12075.

    Google Scholar 

  26. Suffness M, Cordell GA. 1985 Antitumor alkaloids. In: The Alkaloids. Vol. XXV. Brossi A, ed. Academic Press, Florida, 178–188.

    Google Scholar 

  27. Phillips SD, Castle RN. 1981 A review of the chemistry of the antitumor benzo[c]phenanthridine alkaloids nitidine and fagaronine and of the related antitumor alkaloid coralyne. J Heterocycl Chem 18:223–232.

    Google Scholar 

  28. Cushman M, Mohan P, Smith ECR. 1984 Synthesis and biological activity of structural analogues of the anticancer benzophenanthridine alkaloid nitidine chloride. J Med Chem 27:544–547.

    Google Scholar 

  29. Sethi VS. 1976 Inhibition of mammalian and oncornavirus nucleic acid polymerase activities by alkoxybenzophenanthridine alkaloids. Cancer Res 36:2390–2395.

    Google Scholar 

  30. Sethi ML. 1979 Inhibition of reverse transcriptase activity by benzophenanthridine alkaloids. J Nat Prod 42:187–196.

    Google Scholar 

  31. Tan GT, Miller JF, Kinghorn AD, Hughes SH, Pezzuto JM. 1992 HIV-1 and HIV-2 reverse transcriptases: a comparative study of sensitivity to inhibition by selected natural products. Biochem Biophys Res Commun 185:370–378.

    Google Scholar 

  32. Stivers JT, Harris TK, Mildvan AS. 1997 Vaccinia DNA topoisomerase I: evidence supporting a free rotation mechanism for DNA supercoil relaxation. Biochemistry 36:5212–5222.

    Google Scholar 

  33. Berry DE, MacKenzie L, Shultis EA, Chan JA, Hecht SM. 1992 Naturally occurring inhibitors of topoisomerase I-mediated DNA relaxation. J Org Chem 57:420–422.

    Google Scholar 

  34. Matteucci M, Lin KY, Huang T, et al. 1997 Sequence-specific targeting of duplex DNA using a camptothecin-triple helix forming oligonucleotide conjugate and topoisomerase I. J Am Chem Soc 119: 6939–6940.

    Google Scholar 

  35. Hertzberg RP, Busby RW, Caranfa MJ, et al. 1990 Irreversible trapping of the DNA-topoisomerase I covalent complex. J Biol Chem 265:19287–19295.

    Google Scholar 

  36. Pommier Y, Kohlhagen G, Kohn KW, Leteurtre F, Wani MC, Wall ME. 1995 Interaction of an alkylating camptothecin derivative with a DNA base at topoisomerase I-DNA cleavage sites. Proc Natl Acad Sci USA 92:8861–8865.

    Google Scholar 

  37. Fan Y, Weinstein JN, Kohn KW, Shi LM, Pommier Y. 1998 Molecular modeling studies of the DNA-topoisomerase I ternary cleavable complex with camptothecin. J Med Chem 41:2216–2226.

    Google Scholar 

  38. Kerrigan JE, Pilch DS. 2001 A structural model for the ternary cleavable complex formed between human topoisomerase I, DNA, and camptothecin. Biochemistry 40:9792–9798.

    Google Scholar 

  39. Redinbo MR, Stewart L, Kuhn P, Champoux JJ, Hol WG. 1998 Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA. Science 279:1504–1513.

    Google Scholar 

  40. Fiorani P, Bjornsti MA. 2000 Mechanisms of DNA topoisomerase I-induced cell killing in the yeast. In: The camptothecins. Unfolding their anticancer potential. Vol. 922. Liehr JG, Giovanella BC, Verschraegen CF, eds. New York Academy of Sciences, New York, 65–75.

    Google Scholar 

  41. Cornish VW, Kaplan MI, Veenstra DL, Kollman PA, Schultz PG. 1994 Stabilizing and destabilizing effects of placing β-branched amino acids in protein α-helices. Biochemistry 33:12202–12031.

    Google Scholar 

  42. Thorson JS, Chapman E, Schultz PG. 1995 Analysis of hydrogen bonding strengths in proteins using unnatural amino acids. J Am Chem Soc 117:9361–9362.

    Google Scholar 

  43. Sonar S, Liu XM, Lee CP, et al. 1995 Site-directed isotope labeling and FT-IR spectroscopy: the Tyr 185/Pro peptide bond of bacteriorhodopsin is perturbed during the primary photoreaction. J Am Chem Soc 117:11614–11615.

    Google Scholar 

  44. Hohsaka T, Ashizuka S, Murakami H, Sisido M. 1996 Incorporation of nonnatural amino acids into streptavidin through in vitro frame-shift suppression. J Am Chem Soc 118:9778–9779.

    Google Scholar 

  45. Mamaev SV, Laikhter AL, Arslan T, Hecht SM. 1996 Firefly luciferase: alteration of the color of emitted light resulting from substitutions at position 286. J Am Chem Soc 118:7243–7244.

    Google Scholar 

  46. Karginov VA, Mamaev SV, An H, et al. 1997 Probing the role of an active site aspartic acid in dihydrofolate reductase. J Am Chem Soc 119:8166–8176.

    Google Scholar 

  47. Steward LE, Collins CS, Gilmore MA, Carlson JE, Ross JBA, Chamberlin AR. 1997 In vitro site-specific incorporation of fluorescent probes into β-galactosidase. J Am Chem Soc 119:6–11.

    Google Scholar 

  48. England PM, Lester HA, Davidson N, Dougherty DA. 1997 Photochemical proteolysis applied to ion channels in vivo. Proc Natl Acad Sci USA 94:11025–11030.

    Google Scholar 

  49. Schimke RT, Sherwood SW, Hill AB, Johnston RN. 1986 Overreplication and recombination of DNA in higher eukaryotes: potential consequences and biological implications. Proc Natl Acad Sci USA 83:2157–2161.

    Google Scholar 

  50. Landy A. 1989 Dynamic, structural, and regulatory aspects of lambda site-specific recombination. Annu Rev Biochem 58:913–949.

    Google Scholar 

  51. Ikeda H. 1990 DNA topoisomerase-mediated illegitimate recombination. In: DNA Topology and Its Biological Effects. Cozzarelli NR, Wang JC, eds. Cold Spring Harbor Laboratory Press, New York, 341–359.

    Google Scholar 

  52. Shuman S. 1991 Recombination mediated by vaccinia virus DNA topoisomerase I in Escherichia coli is sequence specific. Proc Natl Acad Sci USA 88:10104–10108.

    Google Scholar 

  53. Bullock PW, Forrester W, Botchan M. 1984 DNA sequence studies of simian virus 40 chromosomal excision and integration in rat cells. J Mol Biol 174:55–84.

    Google Scholar 

  54. Bullock P, Champoux JJ, Botchan M. 1985 Association of crossover points with topoisomerase I cleavage sites: a model for nonhomologous recombination. Science 230:954–958.

    Google Scholar 

  55. Henningfeld KA, Hecht SM. 1995 Topoisomerase I-mediated illegitimate recombination with duplex DNA substrates containing branches, nicks and gaps. Biochemistry 34:6120–6129.

    Google Scholar 

  56. Wang X, Wang LK, Kingsbury WD, Johnson RK, Hecht SM. 1998 Differential effects of camptothecin derivatives on topoisomerase I-mediated DNA structure modification. Biochemistry 37:9399–9408.

    Google Scholar 

  57. Rossi F, Labourier E, Forné T, et al. 1996 Specific phosphorylation of SR proteins by mammalian DNA topoisomerase I. Nature 381:80–82.

    Google Scholar 

  58. Tazi J, Rossi F, Labourier E, Gallouzi I, Brunel C, Antoine E. 1997 DNA topoisomerase I: customs officer at the border between DNA and RNA worlds? J Mol Med 75:786–800.

    Google Scholar 

  59. Labourier E, Rossi F, Gallouzi I, Allemand E, Divita G, Tazi J. 1998 Interaction between the N-terminal domain of human DNA topoisomerase I and the arginineserine domain of its substrate determines phosphorylation of SF2/ASF splicing factor. Nucleic Acids Res 26:2955–2962.

    Google Scholar 

  60. Rossi F, Labourier F, Gallouzi I, et al. 1998 The C-terminal domain but not the tyrosine 723 of human DNA topoisomerase I active site contributes to kinase activity. Nucleic Acids Res 26:2963–2970.

    Google Scholar 

  61. Labourier E, Riou JF, Prudhomme M, Carrasco C, Bailly C, Tazi J. 1999 Poisoning of topoisomerase I by an antitumor indolocarbazole drug: stabilization of topoisomerase I-DNA covalent complexes and specific inhibition of the protein kinase activity. Cancer Res 59:52–55.

    Google Scholar 

  62. Anizon F, Belin L, Moreau P, et al. 1997 Syntheses and biological activity (topoisomerases inhibition antitumoral and antimicrobial properties) of rebeccamycin analogues bearing modified sugar moieties and substituted on the imide nitrogen with a methyl group. J Med Chem 40:3456–3465.

    Google Scholar 

  63. Bailly C, Riou JF, Colson P, Houssier C, Rodrigues-Pereira E, Prudhomme M. 1997 DNA cleavage by topoisomerase I in the presence of indolocarbazole derivatives of rebeccamycin. Biochemistry 36:3917–3929.

    Google Scholar 

  64. Wang Z, Castaño IB, De Las Peñas A, Adams, C, Christman MF. 2000 Pol Kappa, a DNA polymerase required for sister chromatid cohesion. Science 289:774–779.

    Google Scholar 

  65. Carson D, Christman MF.2001 Evidence that replication fork components catalyze the establishment of sister chromatid cohesion. Proc Natl Acad Sci USA 98:8270–8275.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Virginia, Charlottesville, VA

    Sidney M. Hecht PhD

  2. Department of Biology, University of Virginia, Charlottesville, VA

    Sidney M. Hecht PhD

Authors
  1. Sidney M. Hecht PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, KY

    Val R. Adams PharmD

  2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY

    Thomas G. Burke PhD

  3. Experimental Therapeutics Program, Lucille P. Markey Cancer Center, University of Kentucky Medical Center, University of Kentucky, Lexington, KY

    Thomas G. Burke PhD

  4. Tigen Pharmaceuticals Inc., Lexington, KY

    Thomas G. Burke PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Hecht, S.M. (2005). Inhibitors of Topoisomerase I Function. In: Adams, V.R., Burke, T.G. (eds) Camptothecins in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59259-866-8:039

Download citation

  • DOI: https://doi.org/10.1385/1-59259-866-8:039

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-027-4

  • Online ISBN: 978-1-59259-866-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation