title: Comparison of preclinical cardiotoxic effects of different ErbB2 inhibitors.
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.
authors.affiliation: Department of Structural and Functional Biology, Federico II University, Naples, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Fedele
authors.forename: Gennaro
authors.initials: G
authors.lastname: Riccio
authors.forename: Carmela
authors.initials: C
authors.lastname: Coppola
authors.forename: Antonio
authors.initials: A
authors.lastname: Barbieri
authors.forename: Maria Gaia
authors.initials: MG
authors.lastname: Monti
authors.forename: Claudio
authors.initials: C
authors.lastname: Arra
authors.forename: Carlo G
authors.initials: CG
authors.lastname: Tocchetti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Alessio
authors.forename: Nicola
authors.initials: N
authors.lastname: Maurea
authors.forename: Claudia
authors.initials: C
authors.lastname: De Lorenzo
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity; D004357:Drug Synergism; D006321:Heart / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D057127:Single-Chain Antibodies / Q000008:administration & dosage / Q000633:toxicity*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004317:Doxorubicin; D018719:Erb-b2 Receptor Tyrosine Kinases; D057127:Single-Chain Antibodies; D000068878:Trastuzumab