Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Topoisomerase I inhibitors: camptothecins and beyond

Nature Reviews Cancer volume 6, pages 789–802 (2006)Cite this article

Key Points

  • Topoisomerase I (TOP1) enzymes are essential in higher eukaryotes, as they are required to relax DNA supercoiling generated by transcription, replication and chromatin remodelling.

  • Topoisomerases are particularly vulnerable to topoisomerase I inhibitors during their cleavage reaction, which is referred to as the 'cleavage complex'.

  • TOP1 can be trapped by anticancer drugs as it cleaves DNA. Moreover, TOP1 can be trapped by endogenous alterations to DNA (mismatches, abasic sites, nicks and adducts) and apoptotic alterations to chromatin.

  • Camptothecin is a natural product of which TOP1 is the only cellular target. Two camptothecin derivatives have recently been approved by the US Food and Drug Administration: topotecan for ovarian and lung cancers and irinotecan for colorectal cancer.

  • Various non-camptothecin inhibitors of TOP1 are in development, including indolocarbazole, phenanthridine and indenoisoquinoline derivatives. Non-camptothecins are expected to be active in cancers that are currently resistant to camptothecins, and to have a greater therapeutic index.

  • Co-crystal structures of TOP1 inhibitors illustrate the interfacial inhibition paradigm by which a small drug molecule can trap conformational intermediates of macromolecular complexes (in the case of TOP1 inhibitors, the TOP1 enzyme and its cleaved DNA substrate).

  • The cytotoxic activity of TOP1 inhibitors is related to the interference of trapped TOP1 cleavage complexes with DNA replication and transcription.

  • Deficiencies in both the checkpoint and DNA-repair pathways determine cellular sensitivity to TOP1 inhibitors. Therefore, the identification of such deficiencies in tumours should guide the rational use of TOP1 inhibitors. Targeting checkpoint and repair pathways should also increase the selectivity of TOP1 inhibitors in tumours that have pre-existing deficiencies in relevant redundant pathways.

Abstract

Nuclear DNA topoisomerase I (TOP1) is an essential human enzyme. It is the only known target of the alkaloid camptothecin, from which the potent anticancer agents irinotecan and topotecan are derived. As camptothecins bind at the interface of the TOP1–DNA complex, they represent a paradigm for interfacial inhibitors that reversibly trap macromolecular complexes. Several camptothecin and non-camptothecin derivatives are being developed to further increase anti-tumour activity and reduce side effects. The mechanisms and molecular determinants of tumour response to TOP1 inhibitors are reviewed, and rational combinations of TOP1 inhibitors with other drugs are considered based on current knowledge of repair and checkpoint pathways that are associated with TOP1-mediated DNA damage.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Relaxation of DNA supercoiling by TOP1-mediated DNA cleavage complexes, and the trapping of TOP1 cleavage complexes by drugs, DNA modifications and during apoptosis.
Figure 2: The chemical structure of camptothecin and its derivatives.
Figure 4: Conversion of TOP1 cleavage complexes into DNA damage by replication-fork collision and transcription.
Figure 3: The atomic structures of camptothecin and non-camptothecin TOP1 inhibitors as they trap a TOP1 cleavage complex and function as interfacial inhibitors.
Figure 5: Molecular pathways involved in cellular responses to TOP1 cleavage complexes.

Similar content being viewed by others

References

  1. Morham, S., Kluckman, K. D., Voulomanos, N. & Smithies, O. Targeted disruption of the mouse topoisomerase I gene by camptothecin selection. Mol. Cell. Biol. 16, 6804–6809 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Zhang, C. X., Chen, A. D., Gettel, N. J. & Hsieh, T. S. Essential functions of DNA topoisomerase I in Drosophila melanogaster. Dev. Biol. 222, 27–40 (2000).

    CAS  PubMed  Google Scholar 

  3. Christman, M. F., Dietrich, F. S. & Fink, G. R. Mitotic recombination in the rDNA of S. cerevisiae is suppressed by the combined action of DNA Topoisomerase I and II. Cell. 55, 413–425 (1988).

    CAS  PubMed  Google Scholar 

  4. Zhang, H. et al. Human mitochondrial topoisomerase I. Proc. Natl Acad. Sci. USA. 98, 10608–10613. (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhang, H., Meng, L. H., Zimonjic, D. B., Popescu, N. C. & Pommier, Y. Thirteen-exon-motif signature for vertebrate nuclear and mitochondrial type IB topoisomerases. Nucleic Acids Res. 32, 2087–2092 (2004). The first report to show that TOP1mt is ubiquitous in vertebrates and probably arose from the duplication of a common ancestor gene that is still found in chordates.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Champoux, J. J. DNA topoisomerases: structure, function, and mechanism. Annu. Rev. Biochem. 70, 369–413 (2001). A detailed review of DNA topoisomerases.

    CAS  PubMed  Google Scholar 

  7. Wang, J. C. Cellular roles of DNA topoisomerases: a molecular perspective. Nature Rev. Mol. Cell Biol. 3, 430–440 (2002). A thoughful perspective on the functions of DNA topoisomerases.

    CAS  Google Scholar 

  8. Pommier, Y. et al. Repair of topoisomerase I-mediated DNA damage. Prog. Nucleic Acid Res. Mol. Biol. 81, 179–229 (2006). This detailed review focuses on the molecular and genetic repair mechanism and the yeast orthologue genes that are involved in the repair of TOP1 covalent complexes.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Stewart, L., Redinbo, M. R., Qiu, X., Hol, W. G. J. & Champoux, J. J. A model for the mechanism of human topoisomerase I. Science 279, 1534–1541 (1998).

    CAS  PubMed  Google Scholar 

  10. Lesher, D. T., Pommier, Y., Stewart, L. & Redinbo, M. R. 8-Oxoguanine rearranges the active site of human topoisomerase I. Proc. Natl Acad. Sci. USA 99, 12102–12107 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Staker, B. L. et al. The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc. Natl Acad. Sci. USA 99, 15387–15392 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Koster, D. A., Croquette, V., Dekker, C., Shuman, S. & Dekker, N. H. Friction and torque govern the relaxation of DNA supercoils by eukaryotic topoisomerase IB. Nature. 434, 671–674 (2005). Provides direct evidence of the controlled rotation of DNA in TOP1ccs using single-molecule analyses.

    CAS  PubMed  Google Scholar 

  13. Xu, C.-J., Grainge, I., Lee, J., Harshey, R. M. & Jayaram, M. Unveiling two distinct ribonuclease activities and a topoisomerase activity in a site-specific DNA recombinase. Mol. Cell. 1, 729–739 (1998).

    CAS  PubMed  Google Scholar 

  14. Pourquier, P., Jensen, A. D., Gong, S. S., Pommier, Y. & Rogler, C. E. Human DNA topoisomerase I-mediated cleavage and recombination of duck hepatitis B virus DNA in vitro. Nucleic Acids Res. 27, 1919–1923 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Cheng, C. & Shuman, S. Recombinogenic flap ligation pathway for intrinsic repair of topoisomerase IB-induced double-strand breaks. Mol. Cell. Biol. 20, 8059–8068 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Pourquier, P. & Pommier, Y. Topoisomerase I-mediated DNA damage. Adv. Cancer Res. 80, 189–216 (2001). Reviews the broad range of DNA damages that trap TOP1 and describes the molecular mechanisms involved in the trapping of TOP1.

    CAS  PubMed  Google Scholar 

  17. Pommier, Y. et al. Repair of and checkpoint response to topoisomerase I-mediated DNA damage. Mutat. Res. 532, 173–203 (2003). A detailed review with particular emphasis on the checkpoint and repair pathways that are involved in the cellular responses to TOP1 covalent complexes.

    CAS  PubMed  Google Scholar 

  18. Sordet, O. et al. Apoptotic topoisomerase I-DNA complexes induced by staurosporine-mediated oxygen radicals. J. Biol. Chem. 279, 50499–50504 (2004).

    CAS  PubMed  Google Scholar 

  19. Sordet, O., Khan, Q. A. & Pommier, Y. Apoptotic topoisomerase I-DNA complexes induced by oxygen radicals and mitochondrial dysfunction. Cell Cycle 3, 1095–1097 (2004). Reviews the generality of apoptotic TOP1 covalent complexes.

    CAS  PubMed  Google Scholar 

  20. Sordet, O. et al. Topoisomerase I-DNA complexes contribute to arsenic trioxide-induced apoptosis. J. Biol. Chem. 279, 33968–33975 (2004).

    CAS  PubMed  Google Scholar 

  21. Bertrand, R., Solary, E., Kohn, K. W., O'Connor, P. & Pommier, Y. Induction of a common pathway to apoptosis by staurosporine. Exp. Cell Res. 211, 314–321 (1994). The first report that staurosporine is a potent inducer of apoptosis in various cell types.

    CAS  PubMed  Google Scholar 

  22. Wall, M. E. & Wani, M. C. Camptothecin and taxol: discovery to clinic — thirteenth Bruce F. Cain Memorial Award lecture. Cancer Res. 55, 753–760 (1995).

    CAS  PubMed  Google Scholar 

  23. Hsiang, Y. H., Hertzberg, R., Hecht, S. & Liu, L. F. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J. Biol. Chem. 260, 14873–14878 (1985). The first report to describe TOP1 as the cellular target of camptothecin.

    CAS  PubMed  Google Scholar 

  24. Eng, W. K., Faucette, L., Johnson, R. K. & Sternglanz, R. Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. Mol. Pharmacol. 34, 755–760 (1988). Shows that TOP1 is the only cellular target of camptothecin as TOP1-deficient yeast cells are immune to camptothecin.

    CAS  PubMed  Google Scholar 

  25. Nitiss, J. & Wang, J. C. DNA topoisomerase-targeting antitumor drugs can be studied in yeast. Proc. Natl Acad. Sci. USA 85, 7501–7505 (1988). Shows that TOP1 is the sole target of camptothecin and that yeast can be used for pharmacological studies and drug discovery.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Pommier, Y., Pourquier, P., Urasaki, Y., Wu, J. & Laco, G. Topoisomerase I inhibitors: selectivity and cellular resistance. Drug Resist. Updat. 2, 307–318 (1999).

    CAS  PubMed  Google Scholar 

  27. Hautefaye, P. et al. Synthesis and pharmacological evaluation of novel non-lactone analogues of camptothecin. Bioorg. Med. Chem. Lett. 13, 2731–2735 (2003).

    CAS  PubMed  Google Scholar 

  28. Meng, L.-H., Liao, Z.-Y. & Pommier, Y. Non-camptothecin DNA topoisomerase I inhibitors in cancer chemotherapy. Curr. Topics Med. Chem. 3, 305–320 (2003). Describes in detail the various families of non-camptothecin TOP1 inhibitors.

    CAS  Google Scholar 

  29. Kohlhagen, G., Paull, K., Cushman, M., Nagafufuji, P. & Pommier, Y. Protein-linked DNA strand breaks induced by NSC 314622, a non-camptothecin topoisomerase I poison. Mol. Pharmacol. 54, 50–58 (1998).

    CAS  PubMed  Google Scholar 

  30. Yamashita, Y. et al. Induction of mammalian DNA topoisomerase I-mediated DNA cleavage by antitumor indolocarbazole derivatives. Biochemistry 31, 12069–12075 (1992).

    CAS  PubMed  Google Scholar 

  31. Long, B. H., Rose, W. C., Vyas, D. M., Matson, J. A. & Forenza, S. Discovery of antitumor indolocarbazoles: rebeccamycin, NSC 655649, and fluoroindolocarbazoles. Curr. Med. Chem. Anticancer Agents 2, 255–266 (2002).

    CAS  PubMed  Google Scholar 

  32. Li, T. K. et al. Characterization of ARC-111 as a novel topoisomerase I-targeting anticancer drug. Cancer Res. 63, 8400–8407 (2003).

    CAS  PubMed  Google Scholar 

  33. Morrell, A. et al. Evaluation of indenoisoquinoline topoisomerase I inhibitors using a hollow fiber assay. Bioorg. Med. Chem. Lett. 16, 4395–4399 (2006).

    CAS  PubMed  Google Scholar 

  34. Antony, S. et al. Differential induction of topoisomerase I-DNA cleavage complexes by the indenoisoquinoline MJ-III-65 (NSC 706744) and camptothecin: base sequence analysis and activity against camptothecin-resistant topoisomerases I. Cancer Res. 63, 7428–7435 (2003).

    CAS  PubMed  Google Scholar 

  35. Antony, S. et al. Cellular topoisomerase I inhibition and antiproliferative activity by MJ-III-65 (NSC 706744), an indenoisoquinoline topoisomerase I poison. Mol. Pharmacol. 67, 523–530 (2005).

    CAS  PubMed  Google Scholar 

  36. Leteurtre, F., Fesen, M., Kohlhagen, G., Kohn, K. W. & Pommier, Y. Specific interaction of camptothecin, a topoisomerase I inhibitor, with guanine residues of DNA detected by photoactivation at 365 nm. Biochemistry 32, 8955–8962 (1993).

    CAS  PubMed  Google Scholar 

  37. Jaxel, C., Capranico, G., Kerrigan, D., Kohn, K. W. & Pommier, Y. Effect of local DNA sequence on topoisomerase I cleavage in the presence or absence of camptothecin. J. Biol. Chem. 266, 20418–20423 (1991). The first hypothesis that camptothecin binds at the interface of the TOP1–DNA complex by stacking between the base pairs flanking the DNA cleavage site

    CAS  PubMed  Google Scholar 

  38. Jaxel, C., Kohn, K. W., Wani, M. C., Wall, M. E. & Pommier, Y. 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 (1989).

    CAS  PubMed  Google Scholar 

  39. Staker, B. L. et al. Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex. J. Med. Chem. 48, 2336–2345 (2005).

    CAS  PubMed  Google Scholar 

  40. Marchand, C. et al. A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of topoisomerase I-DNA covalent complexes. Mol. Cancer Ther. 5, 287–295 (2006). Compares the co-crystal structures of TOP1–DNA-drug ternary complexes for camptothecin, topotecan, an indolocarbazole and two indenoisoquinolines.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Chrencik, J. E. et al. Mechanisms of camptothecin resistance by human topoisomerase I mutations. J. Mol. Biol. 339, 773–784 (2004).

    CAS  PubMed  Google Scholar 

  42. Horwitz, S. B. & Horwitz, M. S. Effects of camptothecin on the breakage and repair of DNA during the cell cycle. Cancer Research. 33, 2834–2836 (1973).

    CAS  PubMed  Google Scholar 

  43. O'Connor, P. M. et al. S-Phase population analysis does not correlate with the cytotoxicity of camptothecin and 10, 11-methylen edioxycamptothecin in human colon carcinoma HT-29 cells. Cancer Commun. 3, 233–240 (1991).

    CAS  PubMed  Google Scholar 

  44. Holm, C., Covey, J. M., Kerrigan, D. & Pommier, Y. Differential requirement of DNA replication for the cytotoxicity of DNA topoisomerase I and II inhibitors in Chinese hamster DC3F cells. Cancer Res. 49, 6365–6368 (1989).

    CAS  PubMed  Google Scholar 

  45. Hsiang, Y.-H., Lihou, M. G. & Liu, L. F. Arrest of DNA replication by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res. 49, 5077–5082 (1989).

    CAS  PubMed  Google Scholar 

  46. Snapka, R. M. & Permana, P. A. SV40 DNA replication intermediates: analysis of drugs which target mammalian DNA replication. Bioessays 15, 121–127 (1993).

    CAS  PubMed  Google Scholar 

  47. Strumberg, D. et al. Conversion of topoisomerase I cleavage complexes on the leading strand of ribosomal DNA into 5′-phosphorylated DNA double-strand breaks by replication runoff. Mol. Cell. Biol. 20, 3977–3987 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Redon, C. et al. Histone H2A variants H2AX and H2AZ. Curr. Opin. Genet. Dev. 12, 162–169 (2002).

    CAS  PubMed  Google Scholar 

  49. Furuta, T. et al. Phosphorylation of histone H2AX and activation of Mre11, Rad50, and Nbs1 in response to replication-dependent DNA-double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes. J. Biol. Chem. 278, 20303–20312 (2003). The first description of histone γ-H2AX phosphorylation in response to replication-induced DSB.

    CAS  PubMed  Google Scholar 

  50. Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005).

    CAS  PubMed  Google Scholar 

  51. Rogakou, E. P., Nieves-Neira, W., Boon, C., Pommier, Y. & Bonner, W. M. Initiation of DNA fragmentation during apoptosis induces phosphorylation of H2AX histone at serine 139. J. Biol. Chem. 275, 9390–9395 (2000). The first report showing histone γ-H2AX formation during apoptosis.

    CAS  PubMed  Google Scholar 

  52. Redon, C. et al. Yeast histone 2A serine 129 is essential for the efficient repair of checkpoint-blind DNA damage. EMBO Rep. 4, 1–7 (2003).

    Google Scholar 

  53. Shao, R.-G. et al. Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes. EMBO J. 18, 1397–1406 (1999). Describes the importance of DNA–PK activation and RPA2 phosphorylation in response to replication-induced DSB.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Pommier, Y., Weinstein, J. N., Aladjem, M. I. & Kohn, K. W. Chk2 molecular interaction map and rationale for Chk2 inhibitors. Clin. Cancer Res. 12, 2657–2661 (2006).

    CAS  PubMed  Google Scholar 

  55. Takemura, H. et al. Defective MRE11-dependent activation of Chk2 by ATM in colorectal carcinoma cells in response to replication-dependendent DNA double-strand breaks. J. Biol. Chem. 10 Aug 2006 (doi:10.1074/jbc.M603747200).

  56. Rao, A. et al. Phosphorylation of BLM, dissociation for topoisomerase IIIα and colocalization with γ-H2AX after topoisomerase I-induced replication damage. Mol. Cell Biol. 25, 8925–8937 (2005)

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Shiloh, Y. & Lehmann, A. R. Maintaining integrity. Nature Cell. Biol. 6, 923–928 (2004).

    CAS  PubMed  Google Scholar 

  58. Kastan, M. B. & Bartek, J. Cell-cycle checkpoints and cancer. Nature 432, 316–323 (2004).

    CAS  PubMed  Google Scholar 

  59. Osborn, A. J., Elledge, S. J. & Zou, L. Checking on the fork: the DNA-replication stress-response pathway. Trends Cell Biol. 12, 509–516 (2002).

    CAS  PubMed  Google Scholar 

  60. Merino, A., Madden, K. R., Lane, W. S., Champoux, J. J. & Reinberg, D. DNA topoisomerase I is involved in both repression and activation of transcription. Nature 365, 227–232 (1993).

    CAS  PubMed  Google Scholar 

  61. Shykind, B. M., Kim, J., Stewart, L., Champoux, J. J. & Sharp, P. A. Topoisomerase I enhances TFIID–TFIIA complex assembly during activation of transcription. Genes Dev. 11, 397–407 (1997).

    CAS  PubMed  Google Scholar 

  62. Rossi, F. et al. Specific phosphorylation of SR proteins by mammalian DNA topoisomerase I. Nature 381, 80–82 (1996).

    CAS  PubMed  Google Scholar 

  63. Soret, J. et al. Altered serine/arginine-rich protein phosphorylation and exonic enhancer-dependent splicing in mammalian cells lacking topoisomerase I. Cancer Res. 63, 8203–8211 (2003).

    CAS  PubMed  Google Scholar 

  64. Ljungman, M. & Hanawalt, P. C. The anti-cancer drug camptothecin inhibits elongation but stimulates initiation of RNA polymerase II transcription. Carcinogenesis 17, 31–35 (1996).

    CAS  PubMed  Google Scholar 

  65. Bendixen, C., Thomsen, B., Alsner, J. & Westergaard, O. Camptothecin-stabilized topoisomerase I–DNA adducts cause premature termination of transcription. Biochemistry 29, 5613–5619 (1990).

    CAS  PubMed  Google Scholar 

  66. Collins, I., Weber, A. & Levens, D. Transcriptional consequences of topoisomerase inhibition. Mol. Cell. Biol. 21, 8437–8451 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Khobta, A. et al. Early effects of topoisomerase I inhibition on RNA polymerase II along transcribed genes in human cells. J. Mol. Biol. 357, 127–138 (2006).

    CAS  PubMed  Google Scholar 

  68. Wu, R. S., Kumar, A. & Warner, J. R. Ribosome formation is blocked by camptothecin, a reversible inhibitor of RNA synthesis. Proc. Natl Acad. Sci. USA 68, 3009–3014 (1971).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Rapisarda, A. et al. Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Cancer Res. 64, 1475–1482 (2004).

    CAS  PubMed  Google Scholar 

  70. Daoud, S. S. et al. Impact of p53 knockout and topotecan treatment on gene expression profiles in human colon carcinoma cells: a pharmacogenomic study. Cancer Res. 63, 2782–2793 (2003).

    CAS  PubMed  Google Scholar 

  71. Kharbanda, S. et al. Camptothecin and its derivatives induce expression of the c-jun protooncogene in human myeloid leukemia cells. Cancer Res. 51, 6636–6642 (1991).

    CAS  PubMed  Google Scholar 

  72. Mialon, A. et al. DNA topoisomerase I is a cofactor for c-Jun in the regulation of epidermal growth factor receptor expression and cancer cell proliferation. Mol. Cell. Biol. 25, 5040–5051 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Wu, J. & Liu, L. F. Processing of topoisomerase I cleavable complexes into DNA damage by transcription. Nucleic Acids Res. 25, 4181–4186 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Morris, E. J. & Geller, H. M. Induction of neuronal apoptosis by camptothecin, an inhibitor of DNA topoisomerase-I: evidence for cell cycle-independent toxicity. J. Cell Biol. 134, 757–770 (1996).

    CAS  PubMed  Google Scholar 

  75. Desai, S. D. et al. Transcription-dependent degradation of topoisomerase I–DNA covalent complexes. Mol. Cell. Biol. 23, 2341–2350 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Desai, S. D., Li, T. K., Rodriguez-Bauman, A., Rubin, E. H. & Liu, L. F. Ubiquitin/26S proteasome-mediated degradation of topoisomerase I as a resistance mechanism to camptothecin in tumor cells. Cancer Res. 61, 5926–5932 (2001). The first description of the degradation of TOP1 by the proteasome in response to its trapping on DNA.

    CAS  PubMed  Google Scholar 

  77. Li, X. & Manley, J. L. Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Cell 122, 365–378 (2005).

    CAS  PubMed  Google Scholar 

  78. Pouliot, J. J., Yao, K. C., Robertson, C. A. & Nash, H. A. Yeast gene for a Tyr-DNA phosphodiesterase that repairs topo I covalent complexes. Science 286, 552–555 (1999). The first report of the existence of tyrosyl-DNA-phosphodiesterase activity.

    CAS  PubMed  Google Scholar 

  79. Takashima, H. et al. Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nature Genet. 32, 267–272 (2002).

    CAS  PubMed  Google Scholar 

  80. El-Khamisy, S. F. et al. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature. 434, 108–113 (2005).

    CAS  PubMed  Google Scholar 

  81. Miao, Z. et al. Hereditary ataxia SCAN1 cells are defective for the repair of transcription-dependent topoisomerase I cleavage complexes. DNA Repair (in the press).

  82. Interthal, H. et al. SCAN1 mutant Tdp1 accumulates the enzyme–DNA intermediate and causes camptothecin hypersensitivity. EMBO J. 24, 2224–2233 (2005). Describes the catalytic mechanisms of TDP1 and refers to the co-crystal structures of TDP1 with its DNA–peptide substrate.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Plo, I et al. Association of XRCC1 and tyrosyl DNA phosphodiesterase (Tdp1) for the repair of topoisomerase I-mediated DNA lesions. DNA Repair 2, 1087–1100 (2003). The first report to show the association of TDP1 with XRCC1 in the base-excision repair complex.

    CAS  PubMed  Google Scholar 

  84. Malanga, M. & Althaus, F. R. Poly(ADP-ribose) reactivates stalled DNA topoisomerase I and Induces DNA strand break resealing. J. Biol. Chem. 279, 5244–5248 (2004).

    CAS  PubMed  Google Scholar 

  85. Chatterjee, S., Cheng, M.-F., Trivedi, D., Petzold, S. J. & Berger, N. A. Camptothecin hypersensitivity in poly (adenosine diphosphate-ribose) polymerase-deficient cell lines. Cancer Commun. 1, 389–394 (1989).

    CAS  PubMed  Google Scholar 

  86. Smith, L. M., Willmore, E., Austin, C. A. & Curtin, N. J. The novel poly(ADP-Ribose) polymerase inhibitor, AG14361, sensitizes cells to topoisomerase I poisons by increasing the persistence of DNA strand breaks. Clin. Cancer Res. 11, 8449–8457 (2005).

    CAS  PubMed  Google Scholar 

  87. Mattern, M. R. et al. Relationship between the intracellular effects of camptothecin and the inhibition of DNA topoisomerase I in cultured L1210 cells. Cancer Res. 47, 1793–1798 (1987).

    CAS  PubMed  Google Scholar 

  88. Giovanella, B. C. et al. DNA topoisomerase I-targeted chemotherapy of human colon cancer in xenografts. Science 246, 1046–1048 (1989).

    CAS  PubMed  Google Scholar 

  89. Kaufmann, S. H., Charron, M., Burke, P. J. & Karp, J. E. Changes in topoisomerase I levels and localization during myeloid maturation in vitro and in vivo. Cancer Res. 55, 1255–1260 (1995).

    CAS  PubMed  Google Scholar 

  90. Takemura, H. et al. Mre11 is commonly inactivated in human colon carcinoma cells and is required to stabilize Rad50–Nbs1 and to cooperate with ATM to activate Chk2 in response to replication-dependent DNA double-strand breaks. Proc. Am. Assoc. Cancer Res. 47, 188 (2006).

  91. Kohn, K. W., Aladjem, M. I., Weinstein, J. N. & Pommier, Y. Molecular interaction maps of bioregulatory networks: a general rubric for systems biology. Mol. Biol. Cell 17, 1–13 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Szakacs, G., Paterson, J. K., Ludwig, J. A., Booth-Genthe, C. & Gottesman, M. M. Targeting multidrug resistance in cancer. Nature Rev. Drug Discov. 5, 219–234 (2006).

    CAS  Google Scholar 

  93. Gottesman, M. M., Fojo, T. & Bates, S. E. Multidrug resistance in cancer: role of ATP-dependent transporters. Nature Rev. Cancer 2, 48–58 (2002).

    CAS  Google Scholar 

  94. Chen, A. Y. et al. Camptothecin overcomes MDR1-mediated resistance in human KB carcinoma cells. Cancer Res. 51, 6039–6044 (1991).

    CAS  PubMed  Google Scholar 

  95. Yang, C.-H. J., Horton, J. K., Cowan, K. H. & Schneider, E. Cross-resistance to camptothecin analogues in mitoxantrone-resistant human breast carcinoma cell line is not due to DNA topoisomerase I alterations. Cancer Res. 55, 4004–4009 (1995).

    CAS  PubMed  Google Scholar 

  96. Brangi, M. et al. Camptothecin resistance: role of the ATP binding cassette (ABC) half-transporter, mitoxantrone-resistance (MXR), and potential for glucuronidation in MXR-expressing cells. Cancer Res. 59, 5938–5946 (1999).

    CAS  PubMed  Google Scholar 

  97. Maliepaard, M. et al. Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res. 59, 4559–4563 (1999).

    CAS  PubMed  Google Scholar 

  98. Kawabata, S. et al. Expression and functional analyses of breast cancer resistance protein in lung cancer. Clin. Cancer Res. 9, 3052–3057 (2003).

    CAS  PubMed  Google Scholar 

  99. Reid, R. J., Kauh, E. A. & Bjornsti, M. A. Camptothecin sensitivity is mediated by the pleiotropic drug resistance network in yeast. J. Biol. Chem. 272, 12091–12099 (1997).

    CAS  PubMed  Google Scholar 

  100. Benedetti, P., Benchokroun, Y., Houghton, P. J. & Bjornsti, M.-A. Analysis of camptothecin resistance in yeast: relevance to cancer therapy. Drug Resist. Updat. 1, 176–183 (1998).

    CAS  PubMed  Google Scholar 

  101. Houghton, P. J. et al. Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res. 64, 2333–2337 (2004).

    CAS  PubMed  Google Scholar 

  102. Johnson, F. M. et al. Phase I studies of imatinib mesylate combined with cisplatin and irinotecan in patients with small cell lung carcinoma. Cancer 106, 366–374 (2006).

    CAS  PubMed  Google Scholar 

  103. Pouliot, J. J., Robertson, C. A. & Nash, H. A. Pathways for repair of topoisomerase I covalent complexes in Saccharomyces cerevisiae. Genes Cells 6, 677–687 (2001).

    CAS  PubMed  Google Scholar 

  104. Shao, R.-G. et al. Abrogation of an S-phase checkpoint and potentiation of camptothecin cytotoxicity by 7-hydroxystaurosporine (UCN-01) in human cancer cell lines, possibly influenced by p53. Cancer Res. 57, 4029–4035 (1997).

    CAS  PubMed  Google Scholar 

  105. Graves, P. R. et al. The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01. J. Biol. Chem. 275, 5600–5605 (2000).

    CAS  PubMed  Google Scholar 

  106. Yu, Q. et al. UCN-01 inhibits p53 up-regulation and abrogates γ-radiation-induced G(2)-M checkpoint independently of p53 by targeting both of the checkpoint kinases, Chk2 and Chk1. Cancer Res. 62, 5743–5748 (2002).

    CAS  PubMed  Google Scholar 

  107. Sato, S., Fujita, N. & Tsuruo, T. Interference with PDK–Akt survival signaling pathway by UCN-01 (7- hydroxystaurosporine). Oncogene 21, 1727–1738 (2002).

    CAS  PubMed  Google Scholar 

  108. Fuse, E., Kuwabara, T., Sparreboom, A., Sausville, E. A. & Figg, W. D. Review of UCN-01 development: a lesson in the importance of clinical pharmacology. J. Clin. Pharmacol. 45, 394–403 (2005).

    CAS  PubMed  Google Scholar 

  109. Pommier, Y., Sordet, O., Rao, A., Zhang, H. & Kohn, K. W. Targeting Chk2 kinase: molecular interaction maps and therapeutic rationale. Curr. Pharm. Des. 11, 2855–2872 (2005).

    CAS  PubMed  Google Scholar 

  110. Hickson, I. et al. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 64, 9152–9159 (2004).

    CAS  PubMed  Google Scholar 

  111. Zhao, Y. et al. Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res. 66, 5354–5362 (2006).

    CAS  PubMed  Google Scholar 

  112. Liu, C., Pouliot, J. J. & Nash, H. A. Repair of topoisomerase I covalent complexes in the absence of the tyrosyl-DNA phosphodiesterase Tdp1. Proc. Natl Acad. Sci. USA. 99, 14970–14975 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Vance, J. R. & Wilson, T. E. Yeast Tdp1 and Rad1–Rad10 function as redundant pathways for repairing Top1 replicative damage. Proc. Natl Acad. Sci. USA 99, 13669–13674 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    CAS  PubMed  Google Scholar 

  115. Jagtap, P. & Szabo, C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nature Rev. Drug Discov. 4, 421–440 (2005).

    CAS  Google Scholar 

  116. Liao, Z., Thibaut, L., Jobson, A. & Pommier, Y. Inhibition of human Tyrosyl-DNA Phosphodiesterase (Tdp1) by aminoglycoside antibiotics and ribosome inhibitors. Mol. Pharmacol. 70, 366–372 (2006).

    CAS  PubMed  Google Scholar 

  117. Reinhold, W. C. et al. Apoptotic susceptibility of cancer cells selected for camptothecin resistance: gene expression profiling, functional analysis, and molecular interaction mapping. Cancer Res. 63, 1000–1011 (2003).

    CAS  PubMed  Google Scholar 

  118. Hayward, R. L. et al. Antisense Bcl-xl down-regulation switches the response to topoisomerase I inhibition from senescence to apoptosis in colorectal cancer cells, enhancing global cytotoxicity. Clin. Cancer Res. 9, 2856–2865 (2003).

    CAS  PubMed  Google Scholar 

  119. Shao, R. G. et al. Activation of the Fas pathway independently of Fas ligand during apoptosis induced by camptothecin in p53 mutant human colon carcinoma cells. Oncogene 20, 1852–1859 (2001).

    CAS  PubMed  Google Scholar 

  120. Huang, T. T. et al. NF-κB activation by camptothecin. A linkage between nuclear DNA damage and cytoplasmic signaling events. J. Biol. Chem. 275, 9501–9509 (2000).

    CAS  PubMed  Google Scholar 

  121. Wu, Z. H., Shi, Y., Tibbetts, R. S. & Miyamoto, S. Molecular linkage between the kinase ATM and NF-κB signaling in response to genotoxic stimuli. Science 311, 1141–1146 (2006).

    CAS  PubMed  Google Scholar 

  122. Sordet, O., Khan, Q., Kohn, K. W. & Pommier, Y. Apoptosis induced by topoisomerase inhibitors. Curr. Med. Chem. Anticancer Agents 3, 271–290 (2003).

    CAS  PubMed  Google Scholar 

  123. Richardson, P. G., Mitsiades, C., Hideshima, T. & Anderson, K. C. Proteasome inhibition in the treatment of cancer. Cell Cycle 4, 290–296 (2005).

    CAS  PubMed  Google Scholar 

  124. Catley, L. et al. Proteasomal degradation of topoisomerase I is preceded by c-Jun NH2-terminal kinase activation, Fas up-regulation, and poly(ADP-ribose) polymerase cleavage in SN38-mediated cytotoxicity against multiple myeloma. Cancer Res. 64, 8746–8753 (2004).

    CAS  PubMed  Google Scholar 

  125. Renault, L., Guibert, B. & Cherfils, J. Structural snapshots of the mechanism and inhibition of a guanine nucleotide exchange factor. Nature 426, 525–530 (2003).

    CAS  PubMed  Google Scholar 

  126. Pommier, Y. & Cherfils, J. Interfacial protein inhibition: a nature's paradigm for drug discovery. Trends Pharmacol. Sci. 28, 136–145 (2005). The first description of the interfacial inhibitor paradigm with a drug molecule trapping a complex associating two or more macromolecules.

    Google Scholar 

  127. Pommier, Y. & Marchand, C. Interfacial inhibitors of protein–nucleic acid interactions. Curr. Med. Chem. Anticancer Agents 5, 421–429 (2005).

    CAS  PubMed  Google Scholar 

  128. Gigant, B. et al. Structural basis for the regulation of tubulin by vinblastine. Nature 435, 519–522 (2005).

    CAS  PubMed  Google Scholar 

  129. Clements, P. M. et al. The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4. DNA Repair 3, 1493–1502 (2004).

    CAS  PubMed  Google Scholar 

  130. Smith, P. J., Makinson, T. A. & Watson, J. V. Enhanced sensitivity to camptothecin in ataxia telangiectasia cells and its relationship with the expression of DNA topoisomerase I. Int. J. Radiat. Biol. 55, 217–231 (1989).

    CAS  PubMed  Google Scholar 

  131. Johnson, M. A., Bryant, P. E. & Jones, N. J. Isolation of camptothecin-sensitive Chinese hamster cell mutants: phenotypic heterogeneity within the ataxia telangiectasia-like XRCC8 (irs2) complementation group. Mutagenesis 15, 367–374 (2000).

    CAS  PubMed  Google Scholar 

  132. Cliby, W. A., Lewis, K. A., Lilly, K. K. & Kaufmann, S. H. S phase and G2 arrests induced by topoisomerase I poisons are dependent on ATR kinase function. J. Biol. Chem. 277, 1599–1606 (2002).

    CAS  PubMed  Google Scholar 

  133. Walton, M. I. et al. Constitutive expression of human Bcl-2 modulates nitrogen mustard and camptothecin induced apoptosis. Cancer Res. 53, 1853–1861 (1993).

    CAS  PubMed  Google Scholar 

  134. Fedier, A. et al. The effect of loss of Brca1 on the sensitivity to anticancer agents in p53-deficient cells. Int. J. Oncol. 22, 1169–1173 (2003).

    CAS  PubMed  Google Scholar 

  135. Rahden-Staron, I. I., Szumilo, M., Grosicka, E., Kraakman Van Der Zwet, M. & Zdzienicka, M. Z. Defective Brca2 influences topoisomerase I activity in mammalian cells. Acta Biochim. Pol. 50, 139–144 (2003).

    CAS  PubMed  Google Scholar 

  136. Squires, S., Ryan, A. J., Strutt, H. L. & Johnson, R. T. Hypersensitivity of Cockayne's syndrome cells to camptothecins is associated with the generation of abnormally high levels of double strand breaks in nascent DNA. Cancer Res. 53, 2012–2019 (1993).

    CAS  PubMed  Google Scholar 

  137. Flatten, K. et al. The role of checkpoint kinase 1 in sensitivity to topoisomerase I poisons. J. Biol. Chem. 280, 14349–14355 (2005).

    CAS  PubMed  Google Scholar 

  138. Wang, J. L., Wang, X., Wang, H., Iliakis, G. & Wang, Y. CHK1-regulated S-phase checkpoint response reduces camptothecin cytotoxicity. Cell Cycle 1, 267–272 (2002).

    CAS  PubMed  Google Scholar 

  139. Yu, Q., Rose, J. H., Zhang, H. & Pommier, Y. Antisense inhibition of Chk2/hCds1 expression attenuates DNA damage- induced S and G2 checkpoints and enhances apoptotic activity in HEK-293 cells. FEBS Lett. 505, 7–12 (2001).

    CAS  PubMed  Google Scholar 

  140. Culmsee, C., Bondada, S. & Mattson, M. P. Hippocampal neurons of mice deficient in DNA-dependent protein kinase exhibit increased vulnerability to DNA damage, oxidative stress and excitotoxicity. Brain Res. Mol. Brain Res. 87, 257–262 (2001).

    CAS  PubMed  Google Scholar 

  141. Zheng, L. et al. Novel function of the flap endonuclease 1 complex in processing stalled DNA replication forks. EMBO Rep. 6, 83–89 (2005).

    CAS  PubMed  Google Scholar 

  142. Liu, B. et al. Genomic instability in laminopathy-based premature aging. Nature Med. 11, 780–785 (2005).

    CAS  PubMed  Google Scholar 

  143. Kraakman-van der Zwet, M. et al. Immortalization and characterization of Nijmegen breakage syndrome fibroblasts. Mutat. Res. 434, 17–27 (1999).

    CAS  PubMed  Google Scholar 

  144. Rasouli-Nia, A., Karimi-Busheri, F. & Weinfeld, M. Stable down-regulation of human polynucleotide kinase enhances spontaneous mutation frequency and sensitizes cells to genotoxic agents. Proc. Natl Acad. Sci. USA. 101, 6905–6910 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Godthelp, B. C. et al. Mammalian Rad51C contributes to DNA cross-link resistance, sister chromatid cohesion and genomic stability. Nucleic Acids Res. 30, 2172–2182. (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Gupta, M. et al. Inactivation of p53 increases the cytotoxicity of camptothecin in human colon HCT116 and breast MCF-7 cancer cells. Clin. Cancer Res. 3, 1653–1660 (1997).

    CAS  PubMed  Google Scholar 

  147. Han, Z. et al. Role of p21 in apoptosis and senescence of human colon cancer cells treated with camptothecin. J. Biol. Chem. 277, 17154–17160 (2002).

    CAS  PubMed  Google Scholar 

  148. Lebel, M. & Leder, P. A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of proliferative capacity. Proc. Natl Acad. Sci. USA 95, 13097–13102 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Poot, M., Gollahon, K. A. & Rabinovitch, P. S. Werner syndrome lymphoblastoid cells are sensitive to camptothecin- induced apoptosis in S-phase. Hum. Genet. 104, 10–14 (1999).

    CAS  PubMed  Google Scholar 

  150. Caldecott, K. & Jeggo, P. Cross-sensitivity of γ-ray-sensitive hamster mutants to cross-linking agents. Mutat. Res. 255, 111–121 (1991).

    CAS  PubMed  Google Scholar 

  151. Thacker, J. & Ganesh, A. N. DNA-break repair, radioresistance of DNA synthesis, and camptothecin sensitivity in the radiation-sensitive irs mutants: comparisons to ataxia-telangiectasia cells. Mutat. Res. 235, 49–58 (1990).

    CAS  PubMed  Google Scholar 

  152. Hinz, J. M., Helleday, T. & Meuth, M. Reduced apoptotic response to camptothecin in CHO cells deficient in XRCC3. Carcinogenesis 24, 249–253 (2003).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I wish to thank K. W. Kohn for many years of enjoyable collaboration and inspiration, as well as all current and past members of the Laboratory of Molecular Pharmacology. Special thanks to O. Sordet and Z. Miao for their careful reading of the manuscript and suggestions. This research was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research.

Author information

Authors and Affiliations

  1. Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, 20892-4255, Maryland, USA

    Yves Pommier

Authors
  1. Yves Pommier
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

DATABASES

National Cancer Institute

colon carcinomas

ovarian cancers

lung cancer

OMIM

TFIID–TFIIA

FURTHER INFORMATION

Yves Pommier's home page

Molecular Interactions Maps (MIM) web site

National Cancer Institute Molecular pharmacology discover web site

Glossary

Topoisomerases

Topoisomerases are divided into type I and II. Type I enzymes cleave only one strand of duplex DNA whereas type II enzymes cleave both strands. Type I topoisomerases are further subdivided into type IA and IB. Type IA enzymes cleave the DNA by forming a 5′-phosphotyrosyl covalent bond and relax DNA supercoiling by a strand-passing mechanism, whereas type IB enzymes form a covalent bond with the 3′ end of the DNA, and relax DNA by controlled rotation.

DNA supercoiling

In relaxed normal B-DNA, each strand crosses the other once every 10.4 base pairs with a right-handed turn. DNA is negatively supercoiled ('underwound') when the strands cross each other at more than a 10.4 base-pair interval. DNA is positively supercoiled ('overwound') when the strands cross each other with a base-pair interval less than 10.4.

Nucleophilic attack

A nucleophile is a chemical compound or group that is attracted to nuclei (centres of positive charge) and tends to donate or share electrons. A nucleophilic chemical reaction consists of the donation of electrons from a nucleophile to another species known as an electrophile in order to form a chemical bond. Nucleophiles can take part in nucleophilic substitution, whereby a nucleophile becomes attracted to a full or partial positive charge on an element and displaces the group to which it is bonded.

Chiral centre

From the Greek word cheir (which translates as 'hand' in English) to mean objects that have non-superimposable mirror images. It is synonymous with stereocentre (for instance an asymmetric carbon atom) whose spatial structure determines whether the enantiomer is in the R configuration (from the Latin 'rectus': right) or the S configuration (from the Latin 'sinister': left).

Leucopaenia

Low white-blood-cell count.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pommier, Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer 6, 789–802 (2006). https://doi.org/10.1038/nrc1977

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1977

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing