Evaluation of the complexity of cell cycle effects induced by anticancer drugs

Lupi, Monica (2006). Evaluation of the complexity of cell cycle effects induced by anticancer drugs. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f647

Abstract

The time- and dose-dependence of the blocking activity, cell loss and recycling from block that follow a treatment with anticancer agents is not always easy to interpret, especially because of the superimposition of cytostatic and cytotoxic effects. Their separate quantification, in terms of the cellular control mechanisms that regulate the response to a drug treatment, is important to deeply understand the mode of action of an anticancer compound.

We investigated cell cycle effects induced by different drugs on a cell line growing in vitro with an approach including experimental data coming from cell counting and different flow cytometric techniques and a mathematical model reproducing the perturbed cell growth after drug treatment. In this way we could quantify the effects induced by treatments performed with topotecan, doxorubicin and melphalan on IGROV1 cells, evaluating separately cytostatic and cytotoxic effects. For each one of the considered drugs we obtained and compared a set of parameters describing the time- and dose-dependence of cell cycle effects. These results were compared with those previously published by our group (Sena et al., 1999; Montalenti et al., 1998).

Besides the classical flow cytometric techniques, we used the method of carboxyfluorescein diacetate succinimidyl ester staining to quantify and appreciate the heterogeneity of the effects induced by a treatment on the cells of the same population. The results obtained could be simulated with our mathematical model. In the last part of the project, the previously listed tools were used to obtain two sets of parameters describing the effects induced by a short treatment of cisplatin on HCT-116 and HCT-116 p53-/-. This allowed the quantification of the role of p53 in the cell response to cisplatin treatment, finding that this protein has a more important role in the activation of the apoptosis than in the cytostatic effects induced by this drug.