Skip to main content
SpringerLink
Log in

Topoisomerase Inhibitors

A Review of their Therapeutic Potential in Cancer

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Summary

The nuclear enzymes topoisomerase I and II are critical for DNA function and cell survival, and recent studies have identified these enzymes as cellular targets for several clinically active anticancer drugs. Topoisomerase II inhibitors (anthracyclines, epipodophyllotoxins, etc.) are active against several types of tumours. However, treatment with these drugs often results in the development of the multi-drug resistance. Because topoisomerase II-active drugs have several different modes of action, different mechanisms of resistance, including decreased activation and increased detoxification by glutathione-dependent enzymes, have also been implicated.

Unlike topoisomerase II, topoisomerase I is not a cell cycle-dependent enzyme and, therefore, it is a more desirable cellular target for anticancer drug development. Topoisomerase I inhibitors, such as camptothecin and its derivatives, have shown significant activity against a broad range of tumours and, in general, are not substrates for either the multi-drug-resistance P-170 glycoprotein or the multi-drug-resistance-associated protein. Because of manageable toxicity and encouraging activity against solid tumours, topoisomerase I-active drugs offer promise in the clinical management of human tumours.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. DiMarco A, Zunino F, Silverstrini R, et al. Interactions of some daunorubicin derivatives with deoxyribonucleic acid and their biological properties. Biochem Pharmacol 1971; 20: 1323–8

    Article  CAS  Google Scholar 

  2. Lown WJ, Morgan A, Yen S, et al. Characteristics of the binding of the anticancer agents mitoxanthrone and amentantrone and related structures to deoxyribonucleic acids. Biochemistry 1985; 24: 4028–35

    Article  PubMed  CAS  Google Scholar 

  3. Ross WE, Glaubiger DL, Kohn KW. Protein-associated DNA breaks in cells treated with adriamycin or ellipticin. Biochim Biophys Acta 1978; 519: 23–30

    Article  PubMed  CAS  Google Scholar 

  4. Ross WE, Glaubiger DL, Kohn KW. Qualitative and quantitative aspects of intercalator-iriduced DNA strand breaks. Biochim Biophys Acta 1979; 562: 41–50

    Article  PubMed  CAS  Google Scholar 

  5. Liu LF, Rowe TC, Yang L, et al. Cleavage of DNA by mammalian topoisomerase II. J Biol Chem 1983; 258: 15365–70

    PubMed  CAS  Google Scholar 

  6. Nelson EM, Tewey KM, Liu LF. Mechanism of antitumor drug action: Poisoning of mammalian DNA topoisomerase II on DNA by 4′-(9-acridnylamino)-methyanesulfon-m-anisidide. Proc Natl Acad Sci USA 1984; 81: 1361–5

    Article  PubMed  CAS  Google Scholar 

  7. Tewey KM, Rowe TC, Yang L. et al. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 1984; 226: 466–8

    Article  PubMed  CAS  Google Scholar 

  8. Wang JC. Type I DNA topoisomerases. In: Boyer P, editor. The enzymes. New York: Academic, 1981; 14: 331–44

    CAS  Google Scholar 

  9. Liu LF. DNA topoisomerases: enzymes that catalyze the breaking and rejoining of DNA. Crit Rev Biochem 1983; 15: 1–24

    Article  CAS  Google Scholar 

  10. Rose KM. DNA topoisomerases as targets for chemotherapy. FASEB J 1988; 2: 2474–8

    PubMed  CAS  Google Scholar 

  11. Drlica K, Franco RJ. Inhibitors of DNA topoisomerases. Biochemistry 1988; 27: 2253–9

    Article  PubMed  CAS  Google Scholar 

  12. Beck WT, Danks MK. Mechanisms of resistance to drugs that inhibit DNA topoisomerases. Semin Cancer Biol 1991; 2: 235–44

    PubMed  CAS  Google Scholar 

  13. Pommier Y, Kerrigan D, Hartman KD, et al. Phosphorylation of mammalian DNA topoisomerase I and activation by protein kinase C. J Biol Chem 1990; 265: 9418–22

    PubMed  CAS  Google Scholar 

  14. Drake FH, Hofmann GA, Bartus HG, et al. Biochemical and pharmacological properties of p170 and p180 forms of topoisomerase II. Biochemistry 1989; 28: 8154–60

    Article  PubMed  CAS  Google Scholar 

  15. Woessner RD, Mattern MR, Mirabelli CK, et al. Proliferation- and cell cycle-dependent differences in the expression of the p170 kilodalton and 180 kilodalton forms of topoisomerase II in NIH-3t3 cells. Cell Growth & Differentiation 1991; 2: 209–14

    CAS  Google Scholar 

  16. Wall M, Wani MC, Cooke CE. et al. Plant anti-tumor agents I: the isolation and structure of camptothecin, a novel alkaloidal leukemia and antitumor inhibitor from Camptotheca acuminata. J Am Chem Soc 1966; 88: 3888–90

    Article  CAS  Google Scholar 

  17. Venditti JM, Abbott BJ. Studies on oncolytic agents from natural sources: correlation of activity against animal tumors and clinical effectiveness. Lloydia 1967; 30: 332–5

    Google Scholar 

  18. Hsiang YH, Hertzberg R, Hect S, et al. Camptothecin induces protein-linked DNA breaks via mammalian topoisomerase I. J Biol Chem 1985; 260: 14873–8

    PubMed  CAS  Google Scholar 

  19. Gottlieb JA, Guarino AM, Call JB. et al. Preliminary pharmacological and clinical evaluation of camptothecin sodium (NSC 100880). Cancer Chemother Rep 1970; 54: 461–70

    PubMed  CAS  Google Scholar 

  20. Eckardt JR, Burris HA, Rothenberg ML, et al. Topoisomerase I inhibitors: promising novel compounds. Contemp Oncol 1993; 3: 47–60

    Google Scholar 

  21. Slichenmyer WJ, Rowinsky EK, Donehower RC, et al. The current status of camptothecin and analogues as antitumor agents. J Natl Cancer Inst 1993; 85: 271–91

    Article  PubMed  CAS  Google Scholar 

  22. Dahut W, Brillhart C, Takimoto C, et al. A phase I trial of α- aminocamptothecin (9-AL) in adult patients with solid tumours [abstract no. 345]. ASCO, May 124–17, Dallas, Texas, USA, 1994

  23. Rowinsky EK, Grochow LB, Hendricks CB, et al. Phase I and pharmacological studies of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol 1992; 10: 647–56

    PubMed  CAS  Google Scholar 

  24. Hendricks CB, Rowinsky EK, Grochow LB, et al. Effect of P-glycoprotein expression on the accumulation and cytotoxicity of topotecan (SK&F 10864), a new camptothecin analogue. Cancer Res 1992; 52: 2268–78

    PubMed  CAS  Google Scholar 

  25. Tsuro T, Matsuzaki T, Matsushita M, et al. Antitumor effects of CPT-11, a new derivative of camptothecin, against pleotropic drug-resistant tumors in vitro and in vivo. Cancer Chemother Pharmacol 1988; 21: 71–4

    Google Scholar 

  26. Kawato Y, Aonuma M, Hirota Y, et al. Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res 1991; 51: 4187–91

    PubMed  CAS  Google Scholar 

  27. Ohno R, Okada K, Masaoka T, et al. An early phase II study of CPT-11: a new derivative of camptothecin, for the treatment of leukemia and lymphoma. J Clin Oncol 1990; 8: 1907–10

    PubMed  CAS  Google Scholar 

  28. Masuda N, Fukuoka M, Kusunoki Y, et al. CPT-11: a new derivative of camptothecin for the treatment of refractory or relaspsed small cell lung cancer. J Clin Oncol 1992; 10: 1225–30

    PubMed  CAS  Google Scholar 

  29. Potmesil M, Kirschenbaum S, Israel M, et al. Relationship of adriamycin to the DNA lesions induced in hypoxic and euoxic L1210. Cancer Res 1983; 43: 3629–3

    Google Scholar 

  30. Potmesil M, Israel M, Silver R. Two mechanisms of adriamycin-DNA interactions in L1210 cells. Biochem Pharmacol 1984; 33: 3137–42

    Article  PubMed  CAS  Google Scholar 

  31. Potmesil M, Hsiang YH, Liu LF, et al. Resistance of human leukemic and normal lymphocytes to drug-induced DNA cleavage and low levels of DNA topoisomerase II. Cancer Res 1988; 48: 3537–41

    PubMed  CAS  Google Scholar 

  32. Sinha BK. Free radicals in anticancer drug pharmacology. Chem Biol Interact 1989; 69: 293–317

    Article  PubMed  CAS  Google Scholar 

  33. Sinha BK, Mimnaugh EG. Free radicals and anticancer drug resistance: oxygen free radicals in the mechanisms of drug cytotoxicity and resistance by certain tumors. Free Radic Biol Med 1990; 8: 567–81

    Article  PubMed  CAS  Google Scholar 

  34. Riordan JR, Deuchars K, Kertner K, et al. Amplification of P-glycoprotein in multidrug resistant mammalian cell lines. 1985; 316: 817–9

    CAS  Google Scholar 

  35. Myers CE, Cowan KH, Sinha BK, et al. The phenomenon of pleiotropic drug resistance. In: DeVita VT, Hellman S, Rosenberg SA, editors. Important advance in oncology, Philadelphia: Lippincot Co, 1987: 27-38

  36. Gottesman MM, Pastan I. Resistance to multiple chemotherapeutic agents in human cancer cells. Trends Pharmacol 1988; 5: 140–51

    Google Scholar 

  37. Issell BF, Rudolph AR, Louie AC. Etoposide (VP-16-213). An overview. In: Issell BF, Muggia FM, Carter SK, editors. Etoposide: current status and new developments. Orlando: Academic Press, Inc., 1984: 1-13

  38. Long BH, Musial ST, Brattain MG. Comparison of cytotoxicity and DNA breakage activity of congeners of epipodophyllotoxin including VP-16,213 and VM-26: a quantitative structure-activity relationship. Biochemistry 1984; 23: 1183–8

    Article  PubMed  CAS  Google Scholar 

  39. Sinha BK, Haim N, Dusre L, et al. DNA strand breaks produced by etoposide (VP-16,213) in sensitive and resistant human breast tumor cells: implications for the mechanism of action. Cancer Res 1988; 48: 5096–100

    PubMed  CAS  Google Scholar 

  40. Loike JD, Horwitz SB. Effects of VP-16-213 on the intracellular degradation of DNA in HeLa cells. Biochemistry 1976; 15: 5443–8

    Article  PubMed  CAS  Google Scholar 

  41. Sinha BK, Politi PM, Eliot HE, et al. Structure-activity relationship, cytotoxicity and topoisomerase II-mediated DNA cleavage induced by pendulum ring analogues of VP-16,213. Eur J Cancer 1990; 26: 590–3

    Article  PubMed  CAS  Google Scholar 

  42. Haim N, Nemec J, Roman J, et al. Peroxidase-catalyzed metabolism of etoposide (VP-16,213) and covalent binding of reactive intermediates to cellular macromolecules. Cancer Res 1987; 47: 5835–40

    PubMed  CAS  Google Scholar 

  43. Kalyanaraman B, Nemec J, Sinha BK. Characterization of free radicals produced during oxidation of etoposide (VP-16) and its catechol and quinone derivatives: an ESR study. Biochemistry 1989; 28: 4839–46

    Article  PubMed  CAS  Google Scholar 

  44. Usui N, Sinha BK. Tyrosinase-induced free radical formation from VP-16,213: relationship to cytotoxicity. Free Radic Res Commun 1990; 10: 287–393

    Article  PubMed  CAS  Google Scholar 

  45. Sinha BK, Eliot HE, Kalyanaraman B. Iron-dependent hydroxyl radical formation and DNA damage from dihydroxy VP-16, a novel metabolite of VP-16. FEBS Lett 1988; 227: 240–4

    Article  PubMed  CAS  Google Scholar 

  46. Sinha BK, Antholine WM, Kalyanaraman B, et al. Copper-dependent oxy-radical mediated DNA damage from dihydroxy derivative of etoposide. Biochem Biophys Acta 1990; 1096: 81–3

    Article  PubMed  CAS  Google Scholar 

  47. Politi PM, Arnold SA, Felsted RL, et al. P-glycoprotein-independent mechanism of resistance to VP-16 in multidrug resistant tumor cell lines: pharmacokinetics and photoaffinity studies. Mol Pharmacol 1990; 37: 790–6

    PubMed  CAS  Google Scholar 

  48. Sehested M, Friche E, Jensen PB, et al. Relationship of VP-16 to the classical multidrug resistance phenotype. Cancer Res 1992: 52: 2874–9

    PubMed  CAS  Google Scholar 

  49. Clarysse A, Brugarolas A, Siegenthaley P, et al. Phase II study of α-hydroxy-2N-methylellipticinium acetate. Eur J Cancer Clin Oncol 1984; 20: 243–7

    Article  PubMed  CAS  Google Scholar 

  50. Crespi MD, Ivanier SE, Genovese J, et al. Mitoxanthrone affects topoisomerase activities in human breast cancer cells. Biochim Biophys Res Commun 1986; 136: 521–8

    Article  CAS  Google Scholar 

  51. Cole SPC, Bhardwaj G, Gerlack JH, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 1992; 258: 1650–4

    Article  PubMed  CAS  Google Scholar 

  52. Scheinder E, Horton JK, Yang CH, et al. Multidrug resistanceassociated protein (MRP) overexpression and reduced sensitivity of topoisomerase II human breast carcinoma MCF-7 cell line selected for etoposide resistance. Cancer Res 1994; 54: 152–8

    Google Scholar 

  53. Utsugi T, Mattern MR, Mirabelli CK, et al. Potentiation of topoisomerase inhibitor-induced DNA strand breakage and cytotoxicity by tumor necrosis factor: enhancement of topoisomerase activity as a mechanism of potentiation. Cancer Res 1990; 50: 2636–40

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Biochemical and Molecular Pharmacology Section, Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Building-10, Room 6N-119, NCI, NIH, Bethesda, Maryland, 20892, USA

    Birandra K. Sinha

Authors
  1. Birandra K. Sinha
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sinha, B.K. Topoisomerase Inhibitors. Drugs 49, 11–19 (1995). https://doi.org/10.2165/00003495-199549010-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-199549010-00002

Keywords

Search

Navigation