Primary endothelial damage is the mechanism of cardiotoxicity of tubulin-binding drugs.

The use of tubulin binders (TBs) in the treatment of cancer often is associated with cardiotoxicity, the mechanism of which has not been elucidated. To test the hypothesis that interstitial cells of the myocardium are the primary target of TBs, we evaluated the acute effects of a single iv administration of three reference TBs: colchicine (0.2 and 2 mg/kg), vinblastine (0.

Preclinical biomarkers for a cyclin-dependent kinase inhibitor translate to candidate pharmacodynamic biomarkers in phase I patients.

A genomics-based approach to identify pharmacodynamic biomarkers was used for a cyclin-dependent kinase inhibitory drug. R547 is a potent cyclin-dependent kinase inhibitor with a potent antiproliferative effect at pharmacologically relevant doses and is currently in phase I clinical trials. Using preclinical data derived from microarray experiments, we identified pharmacodynamic biomarkers to test in blood samples from patients in clinical trials.

Temporal gene expression profiling indicates early up-regulation of interleukin-6 in isoproterenol-induced myocardial necrosis in rat.

Gene expression was evaluated in the myocardium of male Wistar rats after a single subcutaneous administration of 0.5 mg of isoproterenol, a beta-adrenergic agonist that causes acute tachycardia with subsequent myocardial necrosis. Histology of the heart, clinical chemistry, and hematology were evaluated at 9 time points (0.

Geldanamycin, an inhibitor of Hsp90, blocks cytoplasmic retention of progesterone receptors and glucocorticoid receptors via their respective ligand binding domains.

Steroid hormone receptors (SHRs), such as glucocorticoid receptors (GR) and progesterone receptors (PR), are shuttling proteins that undergo continuous nuclear import and export. Various mechanisms have been proposed to explain the localization of SHRs. It has been suggested that the ligand-binding domain (LBD) of SHRs is important in determining the subcellular localization.

Model system to study classical nuclear export signals.

Signal-mediated protein transport through the nuclear pore complex is of considerable interest in the field of molecular pharmaceutics. Nuclear localization signals can be used to target genes/antisense delivery systems to the nucleus. Studying nuclear export is useful in enhancing the expression and the efficiency of action of these therapeutic agents.