Skip to main content
SpringerLink
Log in

Anthracyclines and their C-13 alcohol metabolites: growth inhibition and DNA damage following incubation with human tumor cells in culture

  • Original Articles
  • Anthracyclines, Cytotoxicity, DNA Damage, Ldarubicin
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Summary

Anthracyclines are important antitumor agents used in the treatment of solid tumors, lymphomas, and acute lymphoblastic as well as myelocytic leukemias. The clinical utility of agents such as doxorubicin and daunorubicin and their well-characterized cardiotoxicity have prompted many efforts to develop analogs that retain the desired spectrum of activity but are less cardiotoxic. One such analog is idarubicin (4-demethoxydaunorubicin), which is currently under study in the treatment of adult and pediatric leukemias. The major circulating metabolite of idarubicin is the alcohol product of ketoreductase biotransformation, idarubicinol. Following the administration of idarubicin to adult or pediatric patients, systemic exposure to idarubicinol is greater than that to idarubicin. Moreover, we have also documented the presence of idarubicinol in the cerebrospinal fluid of pediatric patients who have received idarubicin. Idarubicinol has been reported to have greater cytotoxic activity than other anthracycline alcohol metabolites, which are regarded as much less active products of metabolism. We therefore evaluated the growth-inhibitory and DNA-damaging activities of idarubicin, daunorubicin, doxorubicin, epirubicin, and their alcohol metabolites against three relevant (CCRF-CEM lymphoblastic leukemia, K562 myelogenous leukemia, and U87-MG glioblastoma) human tumor cell lines. We found that whereas idarubicin was 2–5 times more potent than the other three anthracycline analogs against these tumor cell lines, idarubicinol was 16–122 times more active than the other alcohol metabolites against the same three cell lines. In addition, idarubicinol and the parent drug idarubicin were equipotent, unlike the other anthracycline alcohol metabolites, which were much less cytotoxic than the corresponding parent drugs. We also assessed the ability of the four parent drugs and their alcohol metabolites to induce DNA single-strand breaks. Idarubicin was more potent than the other three anthracycline analogs and idarubicinol was much more effective than the other alcohol metabolites in inducing DNA damage. These studies in human leukemia and human glioblastoma cell lines support the hypothesis that idarubicinol plays an important role in the antitumor activity of idarubicin and that the activities of idarubicin and idarubicinol are related to their ability to damage DNA.

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. Arcamone F, Bernardi L, Giardino P, Patelli B, DiMarco A, Casazza AM, Pratesi G, Reggiani P (1976) Synthesis and antitumor activity of 4-demethoxydaumorubicin, 4-demethoxy-7,9-diepidaunorubicin, and their beta anomers. Cancer Treat Rep 60: 829

    Google Scholar 

  2. Bachur NR, Steele M, Meriwether WD, Hildebrand RC (1976) Cellular pharmacodynamics of several anthracycline antibiotics. J Med Chem 19: 651

    Google Scholar 

  3. Baurain R, Zenebergh A, Trouet A (1978) Cellular uptake and metabolism of daunorubicin as determined by high-performance liquid chromatography, application to L1210 cells. J Chromatogr 157: 331

    Google Scholar 

  4. Belvedere G, Suarato A, Geroni C, Giuliani PC, D'Incalci M (1989) Comparison of intracellular drug retention, DNA damage and cytotoxicity of derivatives of doxorubicin and daunomycin in a human colon adenocarcinoma cell line (LoVo). Biochem Pharmacol 38: 3713

    Google Scholar 

  5. Benedetti SM, Pianezzola E, Fraier D, Castelli MG, Dostert P (1991) Stereoselectivity of idarubicin reduction in various animal species and humans. Xenobiotica 21: 473

    Google Scholar 

  6. Broggini M, Sommacampagna B, Paolini A, Dolfini E, Grazia Donelli M (1986) Comparative metabolism of daunorubicin and 4-demethoxydaunorubicin in mice and rabbits. Cancer Treat Rep 70: 697

    Google Scholar 

  7. Capranico G, De Isabella P, Penco S, Tinelli S, Zunino F (1989) Role of DNA breakage in cytotoxicity of doxorubicin, 9-deoxydoxorubicin, and 4-demethyl-6-deoxydoxorubicin in murine leukemia P388 cells. Cancer Res 49: 2022

    Google Scholar 

  8. Capranico G, Tinelli S, Zunino F (1989) Formation, resealing and persistence of DNA breaks produced by 4-demethoxydaunorubicin in P388 leukemia cells. Chem Biol Interact 72: 113

    Google Scholar 

  9. Casazza AM, Bertazolli C, Pratesi G (1979) Antileukemic activity and cardiac toxicity of 4-demethoxydaunorubicin in mice. Proc Am Assoc Cancer Res 20: 16

    Google Scholar 

  10. Casazza AM, DiMarco A, Bonnadonna G, Bonfonte V, Bertazzoli G, Bellini O, Pratesi G, Sala L, Ballerini L (1980) Effects of modification in position 4 of the chromophore or in portion 4′ of the aminosugar on the antitumor activity and toxicity of daunorubicin and doxorubicin: In: Crooke ST, Reich SD (eds) Anthracyclines: current status and new developments. Academic Press, New York, p 403

    Google Scholar 

  11. Casazza AM, Pratesi G, Giuliani F, DiMarco A (1980) Antileukemic activity of 4-demethoxydaunorubicin in mice. Tumori 66: 549

    Google Scholar 

  12. Casazza AM, Barbieri B, Fumagalli A, Geroni MC (1983) Biologic activity of 4-demethoxy-13-dihydrodaunorubicin (4-dm-13-OH-DNR). Proc Am Assoc Cancer Res 24: 251

    Google Scholar 

  13. Chevillard S, Vielh P, Bastian G, Coppey J (1990) Adriamycin uptake and metabolism in organotypic culture of A549 human adenocarcinoma cells according to the exposure time. J Cancer Res Clin Oncol 116: 633

    Google Scholar 

  14. DiMarco F, Zunino F, Casazza AM (1978) Comparison of biochemical and biological methods in the evaluation of new anthracycline drugs. Antibiot Chemother 23: 12

    Google Scholar 

  15. Dodion P, Sanders C, Rombaut W, Mattelaer MA, Rozencweig M, Stryckmans P, Kenis Y (1987) Effect of daunorubicin, carminomycin, idarubicin and 4-demethoxydaunorubicinol against human normal myeloid stem cells and human malignant cells in vitro. Eur J Clin Oncol 23: 1909

    Google Scholar 

  16. Kerr DJ, Hynds SA, Shepherd J, Packard CJ, Kaye SB (1988) Comparative cellular uptake and cytotoxicity of a complex of daunomycin-low density lipoprotein in human squamous lung tumour cell monolayers. Biochem Pharmacol 37: 3981

    Google Scholar 

  17. Kohn K, Ewig R, Erickson L, Zwelling L (1981) Measurement of strand breaks and crosslinks in DNA by alkaline elution. In: Friedberg EC, Hanawalt PC (eds) DNA repair: a laboratory manual of research techniques. Marcel Dekker, New York, p 379

    Google Scholar 

  18. Limonta M, Biondi A, Giudici G, Specchia G, Catapano C, Masera G, Barbui T, D'Incalci M (1990) Cytotoxicity and DNA damage caused by 4-demethoxydaunorubicin and its metabolite 4-demethoxy-13-hydroxydaunorubicin in human acute myeloid leukemia cells. Cancer Chemother Pharmacol 26: 340

    Google Scholar 

  19. Loveless H, Arena E, Felsted RL, Bachur NR (1978) Comparative mammalian metabolism of Adriamycin and daunorubicin. Cancer Res 38: 593

    Google Scholar 

  20. Myers CE Jr, Chabner BA (1990) Anthracyclines. In: Chabner BA, Collins JM (eds) Cancer chemotherapy: principles and practice. J. B. Lippincott, Philadelphia, p 356

    Google Scholar 

  21. Olson RD, Mushlin PS, Brenner DE, Fleischer S, Cuseck BJ, Chang BK, Boucek RJ Jr (1988) Doxorubicin cardiotoxicity may be caused by its metabolite doxorubicinol. Proc Natl Acad Sci USA 85: 3585

    Google Scholar 

  22. Penco S, Cassinelli G, Vigevani A, Zini P, Rivola G, Arcamone F (1985) Daunorubicin aldo-keto reductases: enantioface differential reduction of the side-chain carbonyl group of antitumor anthracyclines. Correction of the stereochemistry at C(13) of 4-demethoxy-13-dihydrodaunorubicin. Gazz Chim Ital 115: 195

    Google Scholar 

  23. Reid JM, Kuffel MJ, Pendergrass TW, Hammond D, Ames MM (1989) Cytotoxic concentration of idarubicinol, the alcohol metabolite of idarubicin, are present in CSF following administration of idarubicin to children with relapsed leukemia. Proc Am Assoc Cancer Res 30: 250

    Google Scholar 

  24. Reid JM, Pendergrass TW, Krailo MD, Hammond GD, Ames MM (1990) Plasma pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in pediatric leukemia patients. Cancer Res 50: 6525

    Google Scholar 

  25. Ross WE (1985) DNA topoisomerases as targets for cancer therapy. Biochem Pharmacol 34: 4191

    Google Scholar 

  26. Ross WE, Bradley MO (1981) DNA double strand breaks in mammalian cells after exposure to intercalating agents. Biochim Biophys Acta 654: 129

    Google Scholar 

  27. Scholzel C, Van Putten W, Lowenberg B (1986) A comparison of in vitro sensitivity of acute myeloid leukemia precursors to mitoxantrone, 4′-deoxydoxorubicin, 4-demethoxydaunorubicin and daunorubicin. Leuk Res 10: 1455

    Google Scholar 

  28. Schott B, Robert J 61989) Comparative cytotoxicity, DNA synthesis inhibition and drug incorporation of eight anthracyclines in a model of doxorubicin-sensitive and-resistant rat glioblastoma cells. Biochem Pharmacol 38: 167

    Google Scholar 

  29. Schott B, Robert J (1989) Comparative activity of anthracycline 13-dihydro metabolites against rat glioblastoma cells in culture. Biochem Pharmacol 38: 4069

    Google Scholar 

  30. Speth P, Loo F van de, Linssen P, Wessels H, Haanen C (1986) Plasma and human leukemic cell pharmacokinetics of oral and intravenous 4-demethoxydaunomycin. Clin Pharmacol Ther 40: 643

    Google Scholar 

  31. Supino R, Necco A, Dasdia T, Casazza AM, DiMarco A (1977) Relationship between effects on nucleic acid synthesis in cell cultures and cytotoxicity of 4-demethoxy derivatives of daunorubicin and Adriamycin. Cancer Res 37: 4523

    Google Scholar 

  32. Szmigiero L, Erickson L, Ewig R, Kohn K (1984) DNA strand scission and cross-linking by diaziridinylbenzoquinone (diaziquone) in human cells and relation to cell killing. Cancer Res 44: 4447

    Google Scholar 

  33. Tewey KM, Rowe TC, Yang L, Halligan BD, Liu LF (1984) Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 226: 466

    Google Scholar 

  34. Yesair DW, Tahyer PS, McNitt S, Teague K (1980) Comparative uptake, metabolism and retention of anthracyclines by tumors growing in vitro and in vivo. Eur J Cancer 16: 901

    Google Scholar 

  35. Zanette L, Zucchetti M, Freshi A, Erranti D, Tirelli U, D'Incalci M (1990) Pharmacokinetics of 4-demethoxydaunorubicin in cancer patients. Cancer Chemother Pharmacol 25: 445

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oncology, Division of Oncology Research, Mayo Clinic and Foundation, 200 First Street Southwest, 55905, Rochester, MN, USA

    Mary J. Kuffel, Joel M. Reid & Matthew M. Ames

Authors
  1. Mary J. Kuffel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joel M. Reid
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthew M. Ames
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This research was partially supported by funds from Adria Laboratories and by NCI grant CA 15083, DHHS

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kuffel, M.J., Reid, J.M. & Ames, M.M. Anthracyclines and their C-13 alcohol metabolites: growth inhibition and DNA damage following incubation with human tumor cells in culture. Cancer Chemother. Pharmacol. 30, 51–57 (1992). https://doi.org/10.1007/BF00686485

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00686485

Keywords

Search

Navigation