Breast Cancer Research and Treatment

, Volume 133, Issue 2, pp 511–521 | Cite as

Comparison of preclinical cardiotoxic effects of different ErbB2 inhibitors

  • Carmine Fedele
  • Gennaro Riccio
  • Carmela Coppola
  • Antonio Barbieri
  • Maria Gaia Monti
  • Claudio Arra
  • Carlo G. Tocchetti
  • Giuseppe D’Alessio
  • Nicola Maurea
  • Claudia De Lorenzo
Preclinical study

Abstract

Two novel human antitumor immunoconjugates, made up of a human anti-ErbB2 scFv, Erbicin, fused with either a human RNase or the Fc region of a human IgG1, are selectively cytotoxic for ErbB2-positive cancer cells in vitro and in vivo. The Erbicin-derived immunoagents (EDIA) target an epitope different from that of trastuzumab, the only humanized antibody currently prescribed for treatment of ErbB2-positive breast cancer (BC). As Trastuzumab has shown cardiotoxic effects, in this study, we evaluated if any side effects were exerted also by EDIA, used as single agents or in combination with anthracyclines. Furthermore, we compared the in vitro and in vivo cardiotoxic effects of EDIA with those of the other available anti-ErbB2 drugs: Trastuzumab, 2C4 (Pertuzumab), and Lapatinib. In this article, we show that EDIA, in contrast with Trastuzumab, 2C4, and Lapatinib, have no toxic effects on human fetal cardiomyocytes in vitro, and do not induce additive toxicity when combined with doxorubicin. Furthermore, EDIA do not impair cardiac function in vivo in mice, as evaluated by Color Doppler echocardiography, whereas Trastuzumab significantly reduces radial strain (RS) at day 2 and fractional shortening (FS) at day 7 of treatment in a fashion similar to doxorubicin. Also 2C4 and Lapatinib significantly reduce RS after only 2 days of treatment, even though they showed cardiotoxic effects less pronounced than those of Trastuzumab. These results strongly indicate that RS could become a reliable marker to detect early cardiac dysfunction and that EDIA could fulfill the therapeutic need of patients ineligible to Trastuzumab treatment because of cardiac dysfunction.

Keywords

ErbB2/HER2 Immunotherapy Cardiotoxicity Breast cancer Herceptin/Trastuzumab 

Notes

Acknowledgments

This study was financially supported by AIRC (Associazione Italiana per la Ricerca sul Cancro), Italy; MIUR (Ministero dell’Università e della Ricerca), Italy. The authors wish to thank Dr Philip Cunnah (Biotecnol, S.A., Portugal) for providing the anti-ErbB2 compact antibody Erb-hcAb produced by PER.C6® cells, Dr Eliana Malara for producing 2C4 antibody from the hybridoma cells, and Dr Elisa Di Pietro for her skilled assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–182PubMedCrossRefGoogle Scholar
  2. 2.
    Stebbing J, Copson E, O’Reilly S (2000) Herceptin (trastuzamab) in advanced breast cancer. Cancer Treat Rev 26(4):287–290PubMedCrossRefGoogle Scholar
  3. 3.
    Baselga J (2000) Current and planned clinical trials with trastuzumab (Herceptin). Semin Oncol 27(5 Suppl 9):27–32PubMedGoogle Scholar
  4. 4.
    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792PubMedCrossRefGoogle Scholar
  5. 5.
    Sparano JA (2001) Cardiac toxicity of trastuzumab (Herceptin): implications for the design of adjuvant trials. Semin Oncol 28(1 Suppl 3):20–27PubMedCrossRefGoogle Scholar
  6. 6.
    Chien KR (2000) Myocyte survival pathways and cardiomyopathy: implications for trastuzumab cardiotoxicity. Semin Oncol 27(6 Suppl 11):9–14 discussion 92–100PubMedGoogle Scholar
  7. 7.
    Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S, Liu Y, Peterson KL, Chen J, Kahn R, Condorelli G, Ross J Jr, Chien KR, Lee KF (2002) ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 8(5):459–465. doi:10.1038/nm0502-459 PubMedCrossRefGoogle Scholar
  8. 8.
    Force T, Krause DS, Van Etten RA (2007) Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer 7(5):332–344. doi:10.1038/nrc2106 PubMedCrossRefGoogle Scholar
  9. 9.
    Burris HA 3rd, Hurwitz HI, Dees EC, Dowlati A, Blackwell KL, O’Neil B, Marcom PK, Ellis MJ, Overmoyer B, Jones SF, Harris JL, Smith DA, Koch KM, Stead A, Mangum S, Spector NL (2005) Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 23(23):5305–5313. doi:10.1200/JCO.2005.16.584 PubMedCrossRefGoogle Scholar
  10. 10.
    Perez EA, Suman VJ, Davidson NE, Martino S, Kaufman PA, Lingle WL, Flynn PJ, Ingle JN, Visscher D, Jenkins RB (2006) HER2 testing by local, central, and reference laboratories in specimens from the North Central Cancer Treatment Group N9831 intergroup adjuvant trial. J Clin Oncol 24(19):3032–3038. doi:10.1200/JCO.2005.03.4744 PubMedCrossRefGoogle Scholar
  11. 11.
    Agus DB, Gordon MS, Taylor C, Natale RB, Karlan B, Mendelson DS, Press MF, Allison DE, Sliwkowski MX, Lieberman G, Kelsey SM, Fyfe G (2005) Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 23(11):2534–2543. doi:10.1200/JCO.2005.03.184 PubMedCrossRefGoogle Scholar
  12. 12.
    Schneider JW, Chang AY, Rocco TP (2001) Cardiotoxicity in signal transduction therapeutics: erbB2 antibodies and the heart. Semin Oncol 28(5 Suppl 16):18–26PubMedCrossRefGoogle Scholar
  13. 13.
    De Lorenzo C, Palmer DB, Piccoli R, Ritter MA, D’Alessio G (2002) A new human antitumor immunoreagent specific for ErbB2. Clin Cancer Res 8(6):1710–1719PubMedGoogle Scholar
  14. 14.
    De Lorenzo C, Arciello A, Cozzolino R, Palmer DB, Laccetti P, Piccoli R, D’Alessio G (2004) A fully human antitumor immunoRNase selective for ErbB-2-positive carcinomas. Cancer Res 64(14):4870–4874PubMedCrossRefGoogle Scholar
  15. 15.
    De Lorenzo C, Tedesco A, Terrazzano G, Cozzolino R, Laccetti P, Piccoli R, D’Alessio G (2004) A human, compact, fully functional anti-ErbB2 antibody as a novel antitumour agent. Brit J Cancer 91(6):1200–1204. doi:10.1038/sj.bjc.6602110 PubMedGoogle Scholar
  16. 16.
    De Lorenzo C, Cozzolino R, Carpentieri A, Pucci P, Laccetti P, D’Alessio G (2005) Biological properties of a human compact anti-ErbB2 antibody. Carcinogenesis 26(11):1890–1895. doi:10.1093/carcin/bgi146 PubMedCrossRefGoogle Scholar
  17. 17.
    Gelardi T, Damiano V, Rosa R, Bianco R, Cozzolino R, Tortora G, Laccetti P, D’Alessio G, De Lorenzo C (2010) Two novel human anti-ErbB2 immunoagents are active on trastuzumab-resistant tumours. Br J Cancer 102(3):513–519. doi:10.1038/sj.bjc.6605499 PubMedCrossRefGoogle Scholar
  18. 18.
    De Lorenzo C, Troise F, Cafaro V, D’Alessio G (2007) Combinatorial experimental protocols for Erbicin-derived immunoagents and Herceptin. Br J Cancer 97(10):1354–1360. doi:10.1038/sj.bjc.6604022 PubMedCrossRefGoogle Scholar
  19. 19.
    Troise F, Monti M, Merlino A, Cozzolino F, Fedele C, Russo Krauss I, Sica F, Pucci P, D’Alessio G, De Lorenzo C (2011) A novel ErbB2 epitope targeted by human antitumor immunoagents. FEBS J 278(7):1156–1166. doi:10.1111/j.1742-4658.2011.08041.x PubMedCrossRefGoogle Scholar
  20. 20.
    Riccio G, Esposito G, Leoncini E, Contu R, Condorelli G, Chiariello M, Laccetti P, Hrelia S, D’Alessio G, De Lorenzo C (2009) Cardiotoxic effects, or lack thereof, of anti-ErbB2 immunoagents. FASEB J 23(9):3171–3178. doi:10.1096/fj.09-131383 PubMedCrossRefGoogle Scholar
  21. 21.
    Moens AL, Takimoto E, Tocchetti CG, Chakir K, Bedja D, Cormaci G, Ketner EA, Majmudar M, Gabrielson K, Halushka MK, Mitchell JB, Biswal S, Channon KM, Wolin MS, Alp NJ, Paolocci N, Champion HC, Kass DA (2008) Reversal of cardiac hypertrophy and fibrosis from pressure overload by tetrahydrobiopterin: efficacy of recoupling nitric oxide synthase as a therapeutic strategy. Circulation 117(20):2626–2636. doi:10.1161/CIRCULATIONAHA.107.737031 PubMedCrossRefGoogle Scholar
  22. 22.
    Peng Y, Popovic ZB, Sopko N, Drinko J, Zhang Z, Thomas JD, Penn MS (2009) Speckle tracking echocardiography in the assessment of mouse models of cardiac dysfunction. Am J Physiol 297(2):H811–H820. doi:10.1152/ajpheart.00385.2009 Google Scholar
  23. 23.
    Cittadini A, Isgaard J, Monti MG, Casaburi C, Di Gianni A, Serpico R, Iaccarino G, Sacca L (2003) Growth hormone prolongs survival in experimental postinfarction heart failure. J Am Coll Cardiol 41(12):2154–2163. doi:10.1016/S0735-1097(03)00483-2 PubMedCrossRefGoogle Scholar
  24. 24.
    de Azambuja E, Bedard PL, Suter T, Piccart-Gebhart M (2009) Cardiac toxicity with anti-HER-2 therapies: what have we learned so far? Target Oncol 4(2):77–88. doi:10.1007/s11523-009-0112-2 PubMedCrossRefGoogle Scholar
  25. 25.
    Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353(16):1673–1684PubMedCrossRefGoogle Scholar
  26. 26.
    Perez EA, Koehler M, Byrne J, Preston AJ, Rappold E, Ewer MS (2008) Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clin Proc 83(6):679–686PubMedGoogle Scholar
  27. 27.
    Cardinale D, Colombo A, Torrisi R, Sandri MT, Civelli M, Salvatici M, Lamantia G, Colombo N, Cortinovis S, Dessanai MA, Nole F, Veglia F, Cipolla CM (2010) Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol 28(25):3910–3916. doi:10.1200/JCO.2009.27.3615 PubMedCrossRefGoogle Scholar
  28. 28.
    Ewer MS, Ewer SM (2010) Troponin I provides insight into cardiotoxicity and the anthracycline-trastuzumab interaction. J Clin Oncol 28(25):3901–3904. doi:10.1200/JCO.2010.30.6274 PubMedCrossRefGoogle Scholar
  29. 29.
    Jassal DS, Han SY, Hans C, Sharma A, Fang T, Ahmadie R, Lytwyn M, Walker JR, Bhalla RS, Czarnecki A, Moussa T, Singal PK (2009) Utility of tissue Doppler and strain rate imaging in the early detection of trastuzumab and anthracycline mediated cardiomyopathy. J Am Soc Echocardiogr 22(4):418–424PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Carmine Fedele
    • 1
  • Gennaro Riccio
    • 1
  • Carmela Coppola
    • 3
  • Antonio Barbieri
    • 4
  • Maria Gaia Monti
    • 2
  • Claudio Arra
    • 4
  • Carlo G. Tocchetti
    • 3
  • Giuseppe D’Alessio
    • 1
  • Nicola Maurea
    • 3
  • Claudia De Lorenzo
    • 1
  1. 1.Department of Structural and Functional BiologyFederico II UniversityNaplesItaly
  2. 2.Department of Clinical Medicine, Cardiovascular and Immunological SciencesFederico II UniversityNaplesItaly
  3. 3.Division of CardiologyNational Cancer Institute, G. Pascale FoundationNaplesItaly
  4. 4.Department of Animal Experimental ResearchNational Cancer Institute, G. Pascale FoundationNaplesItaly

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