The increase in c Met mRNA after anti VEGF antibody or sunitinib was accompanied

Although not completely understood, the mechanism of QT interval prolongation has been explained by aberrant cellular trafficking and/or functioning of the human ether ago go K channel. The latter being the most accepted mechanism for the HDACi induced QT interval prolongation. The activation Amuvatinib c-kit 阻害剤 of the hERG K channel leads to ventricular repolarization, hence blocking of this channel may result in QT interval prolongation. HDACi are not the only class of drugs that can interact with the hERG K channel, other drug classes also have that capacity due to the large size of the channels inner cavity and the presence of aromatic residues favoring hydrophobic interactions with lipophilic molecules inside. In addition to the aforementioned mechanisms, drug induced QT prolongation may be caused by increased turnover rate of mature hERG channels from the plasma membrane.<br><br> Though most drug induced QT prolongations have been associated with Afatinib ic50 the hERG channels, other ions channels such Na channel may be involved as well. Lacerda and coworkers reported that Alfuzosin, an 1 adrenergic receptor antagonist with clinical evidence of QT prolongation, did not bind to hERG K channel. Instead, Alfuzosin mechanism of QT prolongation resides in its ability to enhance Na current. Furthermore, the proper functioning of hERG in vivo required the coexpression of many other proteins such as MinK and MinK related peptide 1. Mutations or lack of these peptides have been linked to QT prolongation.<br><br> For drugs known to modulate gene expression, such as HDACi, altering the expression of hERG and any of these genes may lead to QT prolongation even in AG-490 Tyrphostin AG490 the absence of a direct interaction with the hERG channels at therapeutic doses. In fact, emerging evidence in the literature suggests that the QT prolongation associated with HDACis may be the consequence of such altered gene expression and possibly the inhibition of specific HDAC isoforms. Therefore, changes in hERG expression or that of the coregulators of hERG activity may represent yet another mechanism of QT prolongation. This and other alternative mechanisms of QT prolongation discussed therein, may explain the findings that SAHA did not affect hERG K channels up to 300 um and that SB939, another hydroxamate based HDACi, did not bind to hERG channels up to 10 um but showed evidence of QT prolongation during Phase I clinical trials.<br><br> A study looking at the impact of HDACis on the expression of hERG and of its coregulators is needed to elucidate other potential mechanisms of drug induced QT prolongation. Although it has been seen in different clinical trials that HDAC inhibition can lead to QT interval prolongation, there is, however, an increased risk in patients with certain predisposing factors such as diabetes mellitus, obesity, hypothyroidism and congenital long QT syndrome. Other risk factors include gender, advanced age, previous cardiovascular and cerebrovascular diseases. In a study by Barbey et al., baseline ECG in cancer patients prior to treatment revealed cardiac abnormalities, such as sinus tachycardia, atrial fibrillation and previous myocardial infarction in 36% of patients.