Cancer Chemotherapy and Pharmacology

, Volume 77, Issue 1, pp 27–33 | Cite as

Impact of dexrazoxane on doxorubicin-induced aneuploidy in somatic and germinal cells of male mice

  • S. M. AttiaEmail author
  • S. F. Ahmad
  • S. A. Bakheet
Original Article



Despite dexrazoxane’s increasing use in mitigating doxorubicin-induced cardiotoxicity, no data are available in the literature on the potential aneugenicity of drug combination. Therefore, detailed evaluation of aneugenic potential of this combination is essential to provide more insights into aneuploidy induction that may play a role in the development of secondary malignancies and reproductive toxicity after treatment with doxorubicin. Thus, our aim was to determine whether dexrazoxane has influence on the aneuploidy induced by doxorubicin in germinal and somatic cells of male mice.


Sperm BrdU-incorporation assay, sperm FISH assay and the bone marrow micronucleus test complemented by FISH assay were used to determine aneuoploidy. Moreover, the formation of 8-OHdG, one of the oxidative DNA damage by-products, has been evaluated.


Dexrazoxane was not aneugenic at the doses tested. Pre-treatment of mice with dexrazoxane significantly reduced doxorubicin-induced aneuploidy in a dose-dependent manner. Doxorubicin induced marked biochemical alterations characteristic of oxidative DNA damage, and prior administration of dexrazoxane before doxorubicin challenge ameliorated this biochemical marker.


This study provides evidence that dexrazoxane has a protective role in the abatement of doxorubicin-induced aneuploidy. This activity resides, at least in part, in its radical scavenger activity. Thus, dexrazoxane can avert secondary malignancies and abnormal reproductive outcomes in cured cancer patients exposed to doxorubicin.


Doxorubicin Dexrazoxane Aneuploidy Oxidative DNA damage Secondary malignancies Birth defects 



This project was funded by the National Plan for Science, Technology and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, Kingdom of Saudi Arabia, Award Number (12-MED2648-02).

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.


  1. 1.
    Hortobagyi GN (1997) Anthracyclines in the treatment of cancer. An overview. Drugs 54(Suppl 4):1–7PubMedCrossRefGoogle Scholar
  2. 2.
    Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57(7):727–741PubMedCrossRefGoogle Scholar
  3. 3.
    Pai VB, Nahata MC (2000) Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf 22(4):263–302PubMedCrossRefGoogle Scholar
  4. 4.
    Fritz B, Aslan M, Kalscheuer V, Ramsing M, Saar K, Fuchs B, Rehder H (2001) Low incidence of UPD in spontaneous abortions beyond the 5th gestational week. Eur J Hum Genet EJHG 9(12):910–916. doi: 10.1038/sj.ejhg.5200741 PubMedCrossRefGoogle Scholar
  5. 5.
    Ganapathi R, Hoeltge G, Casey G, Grabowski D, Neelon R, Ford J (1996) Acquisition of doxorubicin resistance in human leukemia HL-60 cells is reproducibly associated with 7q21 chromosomal anomalies. Cancer Genet Cytogenet 86(2):116–119PubMedCrossRefGoogle Scholar
  6. 6.
    Aly MS, Othman OE, El Nahas SM (1999) Specific numerical chromosomal aberrations induced by adriamycin. Environ Mol Mutagen 33(2):161–166PubMedCrossRefGoogle Scholar
  7. 7.
    Theodore C, Bayle C, Bernheim A, Wibault P (2002) Secondary leukaemia after treating advanced bladder cancer with methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy and radiotherapy. BJU Int 90(4):470–471PubMedCrossRefGoogle Scholar
  8. 8.
    Attia SM (2008) Mutagenicity of some topoisomerase II-interactive agents. Saudi Pharm J 16:1–24Google Scholar
  9. 9.
    Attia SM (2011) Comparative aneugenicity of doxorubicin and its derivative idarubicin using fluorescence in situ hybridization techniques. Mutat Res 715(1–2):79–87. doi: 10.1016/j.mrfmmm.2011.07.012 PubMedCrossRefGoogle Scholar
  10. 10.
    Buss JL, Hasinoff BB (1993) The one-ring open hydrolysis product intermediates of the cardioprotective agent ICRF-187 (dexrazoxane) displace iron from iron-anthracycline complexes. Agents Actions 40(1–2):86–95PubMedCrossRefGoogle Scholar
  11. 11.
    van Dalen EC, Caron HN, Dickinson HO, Kremer LC (2005) Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev. doi: 10.1002/14651858.CD003917.pub2 PubMedGoogle Scholar
  12. 12.
    Pearlman M, Jendiroba D, Pagliaro L, Keyhani A, Liu B, Freireich EJ (2003) Dexrazoxane in combination with anthracyclines lead to a synergistic cytotoxic response in acute myelogenous leukemia cell lines. Leuk Res 27(7):617–626PubMedCrossRefGoogle Scholar
  13. 13.
    Jones RL (2008) Utility of dexrazoxane for the reduction of anthracycline-induced cardiotoxicity. Expert Rev Cardiovasc Ther 6(10):1311–1317. doi: 10.1586/14779072.6.10.1311 PubMedCrossRefGoogle Scholar
  14. 14.
    Herman EH, Hasinoff BB, Zhang J, Raley LG, Zhang TM, Fukuda Y, Ferrans VJ (1995) Morphologic and morphometric evaluation of the effect of ICRF-187 on bleomycin-induced pulmonary toxicity. Toxicology 98(1–3):163–175PubMedCrossRefGoogle Scholar
  15. 15.
    Hasinoff BB, Kala SV (1993) The removal of metal ions from transferrin, ferritin and ceruloplasmin by the cardioprotective agent ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] and its hydrolysis product ADR-925. Agents Actions 39(1–2):72–81PubMedCrossRefGoogle Scholar
  16. 16.
    Hasinoff BB, Kuschak TI, Yalowich JC, Creighton AM (1995) A QSAR study comparing the cytotoxicity and DNA topoisomerase II inhibitory effects of bisdioxopiperazine analogs of ICRF-187 (dexrazoxane). Biochem Pharmacol 50(7):953–958PubMedCrossRefGoogle Scholar
  17. 17.
    Conde-Estevez D, Mateu-de Antonio J (2014) Treatment of anthracycline extravasations using dexrazoxane. Clin Transl Oncol 16(1):11–17. doi: 10.1007/s12094-013-1100-7 PubMedCrossRefGoogle Scholar
  18. 18.
    Sen S (2000) Aneuploidy and cancer. Curr Opin Oncol 12(1):82–88PubMedCrossRefGoogle Scholar
  19. 19.
    Bakheet SA, Attia SM, Al-Rasheed NM, Al-Harbi MM, Ashour AE, Korashy HM, Abd-Allah AR, Saquib Q, Al-Khedhairy AA, Musarrat J (2011) Salubrious effects of dexrazoxane against teniposide-induced DNA damage and programmed cell death in murine marrow cells. Mutagenesis 26(4):533–543. doi: 10.1093/mutage/ger013 PubMedCrossRefGoogle Scholar
  20. 20.
    Attia SM, Al-Anteet AA, Al-Rasheed NM, Alhaider AA, Al-Harbi MM (2009) Protection of mouse bone marrow from etoposide-induced genomic damage by dexrazoxane. Cancer Chemother Pharmacol 64(4):837–845. doi: 10.1007/s00280-009-0934-8 PubMedCrossRefGoogle Scholar
  21. 21.
    Schmid TE, Attia S, Baumgartner A, Nuesse M, Adler ID (2001) Effect of chemicals on the duration of male meiosis in mice detected with laser scanning cytometry. Mutagenesis 16(4):339–343PubMedCrossRefGoogle Scholar
  22. 22.
    Attia SM, Schmid TE, Badary OA, Hamada FM, Adler ID (2002) Molecular cytogenetic analysis in mouse sperm of chemically induced aneuploidy: studies with topoisomerase II inhibitors. Mutat Res 520(1–2):1–13PubMedCrossRefGoogle Scholar
  23. 23.
    Krishna G, Hayashi M (2000) In vivo rodent micronucleus assay: protocol, conduct and data interpretation. Mutat Res 455(1–2):155–166PubMedCrossRefGoogle Scholar
  24. 24.
    Attia SM (2009) Use of centromeric and telomeric DNA probes in in situ hybridization for differentiation of micronuclei induced by lomefloxacin. Environ Mol Mutagen 50(5):394–403. doi: 10.1002/em.20451 PubMedCrossRefGoogle Scholar
  25. 25.
    Attia SM (2007) The genotoxic and cytotoxic effects of nicotine in the mouse bone marrow. Mutat Res 632(1–2):29–36. doi: 10.1016/j.mrgentox.2007.04.010 PubMedCrossRefGoogle Scholar
  26. 26.
    Attia SM, Kliesch U, Schriever-Schwemmer G, Badary OA, Hamada FM, Adler ID (2003) Etoposide and merbarone are clastogenic and aneugenic in the mouse bone marrow micronucleus test complemented by fluorescence in situ hybridization with the mouse minor satellite DNA probe. Environ Mol Mutagen 41(2):99–103. doi: 10.1002/em.10135 PubMedCrossRefGoogle Scholar
  27. 27.
    Attia SM (2012) Influence of resveratrol on oxidative damage in genomic DNA and apoptosis induced by cisplatin. Mutat Res 741(1–2):22–31. doi: 10.1016/j.mrgentox.2011.10.008 PubMedCrossRefGoogle Scholar
  28. 28.
    Ling YH, El-Naggar AK, Priebe W, Perez-Soler R (1996) Cell cycle-dependent cytotoxicity, G2/M phase arrest, and disruption of p34cdc2/cyclin B1 activity induced by doxorubicin in synchronized P388 cells. Mol Pharmacol 49(5):832–841PubMedGoogle Scholar
  29. 29.
    Murray AW (1992) Creative blocks: cell-cycle checkpoints and feedback controls. Nature 359(6396):599–604. doi: 10.1038/359599a0 PubMedCrossRefGoogle Scholar
  30. 30.
    Adler ID (1993) Synopsis of the in vivo results obtained with the 10 known or suspected aneugens tested in the CEC collaborative study. Mutat Res 287(1):131–137PubMedCrossRefGoogle Scholar
  31. 31.
    Pytel D, Wysocki T, Majsterek I (2006) Comparative study of DNA damage, cell cycle and apoptosis in human K562 and CCRF-CEM leukemia cells: role of BCR/ABL in therapeutic resistance. Comp Biochem Physiol Toxicol Pharmacol CBP 144(1):85–92. doi: 10.1016/j.cbpc.2006.06.010 CrossRefGoogle Scholar
  32. 32.
    Martin RH, Rademaker AW, Leonard NJ (1995) Analysis of chromosomal abnormalities in human sperm after chemotherapy by karyotyping and fluorescence in situ hybridization (FISH). Cancer Genet Cytogenet 80(1):29–32PubMedCrossRefGoogle Scholar
  33. 33.
    Dhawan A, Kayani MA, Parry JM, Parry E, Anderson D (2003) Aneugenic and clastogenic effects of doxorubicin in human lymphocytes. Mutagenesis 18(6):487–490PubMedCrossRefGoogle Scholar
  34. 34.
    Hofland KF, Thougaard AV, Sehested M, Jensen PB (2005) Dexrazoxane protects against myelosuppression from the DNA cleavage-enhancing drugs etoposide and daunorubicin but not doxorubicin. Clin Cancer Res 11(10):3915–3924. doi: 10.1158/1078-0432.CCR-04-2343 PubMedCrossRefGoogle Scholar
  35. 35.
    Kaneko T, Tahara S, Matsuo M (1996) Non-linear accumulation of 8-hydroxy-2′-deoxyguanosine, a marker of oxidized DNA damage, during aging. Mutat Res 316(5–6):277–285PubMedCrossRefGoogle Scholar
  36. 36.
    Floyd RA (1990) The role of 8-hydroxyguanine in carcinogenesis. Carcinogenesis 11(9):1447–1450PubMedCrossRefGoogle Scholar
  37. 37.
    Valavanidis A, Vlachogianni T, Fiotakis C (2009) 8-hydroxy-2′ -deoxyguanosine (8-OHdG): a critical biomarker of oxidative stress and carcinogenesis. J Environ Sci Health, Part C Environ Carcinog Ecotoxicol Rev 27(2):120–139. doi: 10.1080/10590500902885684 CrossRefGoogle Scholar
  38. 38.
    Grankvist K, Henriksson R (1987) Doxorubicin and epirubicin iron-induced generation of free radicals in vitro. A comparative study. Biosci Rep 7(8):653–658PubMedCrossRefGoogle Scholar
  39. 39.
    Ravi D, Das KC (2004) Redox-cycling of anthracyclines by thioredoxin system: increased superoxide generation and DNA damage. Cancer Chemother Pharmacol 54(5):449–458. doi: 10.1007/s00280-004-0833-y PubMedCrossRefGoogle Scholar
  40. 40.
    Attia SM (2010) Deleterious effects of reactive metabolites. Oxid Med Cell Longev 3(4):238–253PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Junjing Z, Yan Z, Baolu Z (2010) Scavenging effects of dexrazoxane on free radicals. J Clin Biochem Nutr 47(3):238–245. doi: 10.3164/jcbn.10-64 PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Galetta F, Franzoni F, Cervetti G, Regoli F, Fallahi P, Tocchini L, Carpi A, Antonelli A, Petrini M, Santoro G (2010) In vitro and in vivo study on the antioxidant activity of dexrazoxane. Biomed Pharmacother 64(4):259–263. doi: 10.1016/j.biopha.2009.06.018 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of Pharmacology and Toxicology, College of PharmacyKing Saud UniversityRiyadhSaudi Arabia
  2. 2.Department of Pharmacology and Toxicology, College of PharmacyAl-Azhar UniversityCairoEgypt

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