Generation of Dose-Response Curves and Improved IC50s for PARP Inhibitor Nanoformulations.

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors that target DNA damage repair pathways in cancer cells are increasingly attractive for treating several cancers. Determining the half maximal inhibitory concentration (IC50) of these molecular inhibitors in cell lines is crucial for further dosing for in vivo experiments. Typically these in vitro assays are conducted for 24-72h; however, PARP inhibitors exhibit cytotoxicity based on the inability to repair DNA damage and thus the accumulation of deleterious mutations takes place over longer times. Therefore, in order to determine a relevant dose response, the time frame of the assay must be modified to account for the time required for the cells to exhibit effects from the treatment. Here, we describe two techniques for generating both short- and long-term dose-response curves for both free PARP inhibitors and nanoparticle formulations of these drugs.