Modeling the cytotoxicity of cisplatin

Abstract

Cisplatin has been the mainstay of chemotherapeutic efforts against several types of cancers for over 30 years. However, there is still much that is unknown regarding its mechanism of action. The several serious side effects of cisplatin therapy and the lack of consensus regarding the ideal dosage regimen necessitate the development of a quantitative model for cisplatin action. A first-level mathematical model is presented for the cytotoxicity of cisplatin which predicts the survival of cancer cells when subjected to a given dose of this antitumor drug. This model comprises of (i) an uptake model that describes the movement of cisplatin molecules from the extracellular medium to the cell nucleus and the formation (and repair) of cisplatin-DNA adducts and (ii) a tolerance model that relates the quantity of cisplatin-DNA adducts formed inside the cell nuclei in a tumor to the fraction of tumor cells that are killed. The predictions of the model are in good agreement with in vitro experimental data obtained for carcinoma cell lines. To the best of our knowledge, this is the first model combining the uptake of cisplatin (consistent with the biochemical mechanism of action) with cell death (based on cisplatin-DNA adducts). It predicts a Pareto-type set of dosage regimen (dosage, C_ext, vs exposure time, t_exp) of cisplatin to obtain a desired chemotherapeutic efficacy. Some reported patient-data is consistent with this prediction.