RT Journal Article
SR Electronic
T1 Model for Time Dependency of Cytotoxic Effect of CHS 828 in Vitro Suggests Two Different Mechanisms of Action
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1140
OP 1147
VO 299
IS 3
A1 Hassan, Saadia B.
A1 Jonsson, Elin
A1 Larsson, Rolf
A1 Karlsson, Mats O.
YR 2001
UL http://jpet.aspetjournals.org/content/299/3/1140.abstract
AB CHS 828 is a novel drug belonging to the cyanoguanidines. It has shown promising anticancer activity in many preclinical systems and is currently in early clinical trials. Our aim in this study was to assess the growth inhibitory effect of CHS 828 in comparison with paclitaxel, etoposide, and topotecan as a function of concentration and time. U937 GTB, RPMI 8226/S, MDA 231, primary cells from chronic lymphocytic leukemia, and normal mononuclear cells 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 fluorometric 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-effect curves, and plateau with time were studied. The log IC50 for CHS 828 decreased with log time in a sigmoid manner for all cell types tested. Although very steep at short and long incubation, the concentration-effect curves became shallow at intermediate times. The log IC50 for etoposide and topotecan was decreased with log time in a sigmoid manner. The log IC50 for paclitaxel decreased linearly with log time. The information obtained from modeling the cytotoxic effect of CHS 828 and changes of IC50 and slope parameters with exposure time suggests a heterogeneous cell response to CHS 828. This could indicate two distinct mechanisms of induction of cell death. The American Society for Pharmacology and Experimental Therapeutics