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Cytostatic and Cytotoxic Effects of Topotecan Decoded by a Novel Mathematical Simulation Approach

Biophysics Unit, Laboratory of Anticancer Pharmacology, Department of Oncology, Istituto di Ricerche Farmacologiche "Mario Negri," Milano, Italy

Topotecan (TPT) is a topoisomerase I inhibitor, and like the other drugs of this family, it is believed to act in a specific way on cells in S phase at the time of treatment. Exploiting a new method, coupling a particular experimental plan with computer simulation, a complete quantitative study of the time dependence and dose dependence of the activity of cell cycle controls has become feasible, and the overall scenario of events after treatment can be reconstructed in detail. We were able to demonstrate that the response of an ovarian cancer cell line to 1 h of treatment with TPT is not limited to inhibition of DNA synthesis, leading to cell death, but involves G₁ and G₂-M checkpoints. G₁ and G₂-M block, recycling, and death follow specific dose-dependent kinetics, lasting no less than 3 days after treatment. We also found that cells treated outside S phase contribute significantly to the overall activity. The utility of this analysis was demonstrated by reproducing more complex treatment schemes in which low TPT concentrations were applied for 1 h three times at 24-h intervals. In this case, the simulation clarified the origin of the auto-potentiation observed with repeated 0.2 µM treatments, in which the cytotoxicity, particularly against S-phase cells, was higher than the cytotoxicity in cells treated with 10 µM only once. We believe that this approach will help us to understand the complexity and heterogeneity of the response of a cell population to a drug challenge and could help us to establish the rationale for drug scheduling or drug combinations.

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