Model for time dependency of cytotoxic effect of CHS 828 in vitro suggeststwo different mechanisms of action

CHS 828 is a novel drug belonging to the cyanoguanidines. it has shown prom ising anticancer activity in many preclinical systems and is currently in e arly clinical trials. Our aim in this study was to assess the growth inhibi tory effect of CHS 828 in comparison with paclitaxel, etoposide, and topote can as a function of concentration and time. U937 GTB, RPMI 8226/S, MDA 231 , primary cells from chronic lymphocytic leukemia, and normal mononuclear c ells were exposed to CHS 828 and U937 GTB cells were exposed to paclitaxel, etoposide, and topotecan in 18 concentrations for times ranging from 1 to 72 h. Cell survival was measured after 72-h incubation by using the fluorom etric microculture cytotoxicity assay. Nonlinear mixed effect modeling was used to model the concentration-effect curves with a modified Hill equation . Patterns of change of drug potency (IC50), slope of the concentration-eff ect curves, and plateau with time were studied. The log IC50 for CHS 828 de creased with log time in a sigmoid manner for all cell types tested. Althou gh very steep at short and long incubation, the concentration-effect curves became shallow at intermediate times. The log IC50 for etoposide and topot ecan was decreased with log time in a sigmoid manner. The log IC50 for pacl itaxel decreased linearly with log time. The information obtained from mode ling the cytotoxic effect of CHS 828 and changes of IC50 and slope paramete rs with exposure time suggests a heterogeneous cell response to CHS 828. Th is could indicate two distinct mechanisms of induction of cell death.