Cardiotoxicity in signal transduction therapeutics

ErbB2 antibodies and the heart

Jay W. Schneider, Alice Y Chang, Thomas P. Rocco

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Cardiotoxicity is a common and potentially devastating side effect of antineoplastic drug therapy. This empiric observation is seen as paradoxical given that the cardiomyocyte is considered to be a terminally differentiated cell. Despite the fact that these cells do not divide after birth, adult cardiomyocytes may become "innocent bystander" targets of anticancer drugs designed to interfere with cell signaling pathways in rapidly proliferating cells. In breast cancer clinical trials, treatment with the erbB2 receptor antibody trastuzumab combined with anthracyclines has been associated with an increased risk for the development of cardiac pump failure. Trastuzumab/anthracycline cardiomyopathy may be the first clinically significant cardiotoxicity to emerge from signal transduction therapeutics. The erbB2 receptor tyrosine kinase is known to have a critical role in cardiac development. In addition, erbB2 is thought to participate in an important pathway for growth, repair, and survival of adult cardiomyocytes as part of a signaling network that involves neuregulins and the neuregulin receptor erbB4. However, erbB2 levels in the adult heart are low when compared with the levels found in erbB2-overexpressing breast cancer cells that are the intended targets of trastuzumab therapy. Thus, trastuzumab-associated cardiotoxicity must be explained by some alternative mechanism. After confirming that trastuzumab is capable of inducing tyrosine phosphorylation of the human cardiomyocyte erbB2 protein, a novel system for culturing human myocardium was developed in our laboratory. We used this system to study the effects of trastuzumab on human cardiomyocytes in vitro and observed trastuzumab-induced structural and functional changes in human cardiomyocytes that were at least partially reversible with the addition of recombinant neuregulins. The results obtained in these experiments support a direct action of trastuzumab on human cardiomyocytes. In addition, these data provide insight regarding potential molecular mechanisms. Most importantly, these data draw attention to the inherent risk of cardiotoxicity associated with a newly emerging class of antineoplastic drugs that interfere with signal transduction pathways.

Original languageEnglish (US)
Pages (from-to)18-26
Number of pages9
JournalSeminars in Oncology
Volume28
Issue number5 SUPPL. 16
StatePublished - 2001
Externally publishedYes

Fingerprint

Cardiac Myocytes
Signal Transduction
Antibodies
Neuregulins
Anthracyclines
Therapeutics
Antineoplastic Agents
Breast Neoplasms
Cardiotoxicity
Trastuzumab
Receptor Protein-Tyrosine Kinases
Drug-Related Side Effects and Adverse Reactions
Cardiomyopathies
Tyrosine
Myocardium
Heart Failure
Phosphorylation
Observation
Clinical Trials
Parturition

ASJC Scopus subject areas

  • Medicine(all)
  • Hematology
  • Oncology

Cite this

Cardiotoxicity in signal transduction therapeutics : ErbB2 antibodies and the heart. / Schneider, Jay W.; Chang, Alice Y; Rocco, Thomas P.

In: Seminars in Oncology, Vol. 28, No. 5 SUPPL. 16, 2001, p. 18-26.

Research output: Contribution to journalArticle

Schneider, Jay W. ; Chang, Alice Y ; Rocco, Thomas P. / Cardiotoxicity in signal transduction therapeutics : ErbB2 antibodies and the heart. In: Seminars in Oncology. 2001 ; Vol. 28, No. 5 SUPPL. 16. pp. 18-26.
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