Semi-mechanistic description of the in-vitro antiproliferative effect of different antitumour agents

The aim of the present work was to describe the antiproliferative effect of camptothecin (CPT), topotecan (TPT) and cisplatin (CIS) in cultured cells using a semi-mechanistic pharmacodynamic approach. This effect on the growth of DHD-K12PROb cells was modelled as a function of drug concentration and time of exposure using the Gompertz framework. Models reflected two major processes: cell proliferation and cell death/degradation. Antiproliferative effect of CPT and TPT was described as inhibition of cell proliferation, while the effect of CIS was described as stimulation of cell death, including a signal transduction process, reflected as a delay in the onset of drug action. The half-life associated with such a transduction process was estimated to be approximately 27 h. Interestingly, the time profiles of the model predicted a signal transduction process that closely resembled the observed profiles of caspase-3, a protein implicated in CIS-mediated apoptosis. Therefore, the combination of a simple and sensitive design, together with an appropriated modelling strategy, allowed us to explore different mechanisms of action for antitumour agents in cultured cells and to obtain information about the dynamics of signal transduction and the potential use of biomarkers.