Ado trastuzumab emtansine (TDM1) is a novel antibody–drug conjugate consisting of trastuzumab (TRAS) covalently linked to the highly potent microtubule inhibitory agent DM1 via a stable thioether linker. TDM1 is used in metastatic ErbB2 positive breast cancer patients. Although, the potential cardiotoxic effects of TDM1 have not yet been fully elucidated, they can include all the mechanisms of TRAS-related cardiotoxicity, such as changes in Ca2+ regulation. Here, we aim to elucidate whether Ranolazine (RAN), administered after TDM1 treatment, blunts or not cardiotoxicity in vivo and in vitro.
In vitro, human fetal cardiomyocytes (HFC) were treated with TDM1 for 3 days and then treated in the absence or presence of RAN for 3 days. Cell viability was assessed by cell counting and MTT assay. To evaluate cardiac function in vivo, C57/BL6 mice, 2-4 months old, were daily treated with TDM1 (44.4 mg/kg/day). At day 0 and after 7 days, fractional shortening (FS) and ejection fraction (EF) were measured, by M/B mode echocardiography, and radial and longitudinal strain (RS and LS) were evaluated using 2D speckle-stracking. These measurements were repeated after 5 days of RAN treatment (305 mg/Kg/day), started at the end of TDM1 treatment.
RAN reduces TDM1 toxicity in HFC, as evidenced by the higher percentage of viable cells treated with TDM1+ RAN with respect to the cells treated with TDM1 alone (p
Here we show that in vivo RAN post-treatment reduces cardiotoxic effects due to TDM1, as demonstrated by the recovery of FS, EF and LS values. As expected, RAN increases cell viability of HFC treated with TDM1.
Clinical trial identification
Legal entity responsible for the study
Fondi di Ricerca Corrente destinati all' Istituto Nazionale Tumori Pascale - Napoli
All authors have declared no conflicts of interest.