COMPARISON OF CARDIOTOXIC EFFECTS OF DIFFERENT ERB-B2 INHIBITORS AND THEIR ASSOCIATED MECHANISMS
Fedele, Carmine (2011) COMPARISON OF CARDIOTOXIC EFFECTS OF DIFFERENT ERB-B2 INHIBITORS AND THEIR ASSOCIATED MECHANISMS. [Tesi di dottorato] (Inedito)
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The ErbB2 receptor is a proto-oncogene associated with a poor prognosis in breast cancer. Herceptin, the only humanized anti-ErbB2 antibody currently in clinical use, has proved to be an essential tool in the immunotherapy of breast carcinoma, but induces cardiotoxicity. ErbB2 is involved in the growth and survival pathway of adult cardiomyocytes; however its levels in the adult heart are much lower than those found in breast cancer cells, the intended targets of anti-ErbB2 antibodies. Furthermore, Lapatinib, a dual kinase inhibitor of EGFR and ErbB2, and Pertuzumab, a new anti-ErbB2 monoclonal antibody currently in clinical trials, which recognizes an epitope distant from that of Herceptin, have shown relatively low cardiotoxicity in clinical trials. 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 vivo, and target an epitope of ErbB2 different from that of Herceptin. As Herceptin has shown cardiotoxic effects, we evaluated if any side effects were exerted also by Erbicin-derived immunoagents (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: Herceptin, 2C4 (Pertuzumab) and Lapatinib. Here we show that EDIA, in contrast with Herceptin, 2C4 and Lapatinib, have no toxic effects on human fetal cardiomyocytes in vitro, and do not induce additive toxicity when combined with doxorubicin. Moreover, EDIA do not impair cardiac function in vivo in mice, as evaluated by Color Doppler echocardiography, whereas Herceptin significantly reduces radial strain at day 2 and fractional shortening at day 7 of treatment in a fashion similar to doxorubicin. Also 2C4 and Lapatinib significantly reduce radial strain after only two days of treatment, even though they showed cardiotoxic effects less pronounced than those of Herceptin. We investigated also the molecular basis of the different cardiotoxic effects among the ErbB2 inhibitors by testing their effects on the formation of the Neuregulin 1β (HRG)/ErbB2/ErbB4 complex and on the activation of its downstream signaling. We report herein that Erb-hcAb at difference with Herceptin, 2C4 (Pertuzumab) and Lapatinib, does not affect the ErbB2-ErbB4 signaling pathway activated by HRG in cardiac cells. These findings may have important implications for the mechanism and treatment of anti-ErbB2-induced cardiotoxicity, and suggest that EDIA could fulfil the therapeutic need of patients ineligible to Herceptin treatment due to cardiac dysfunction. Furthermore, these results strongly indicate that radial strain could become a reliable marker to detect early cardiac dysfunction.
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