title: The effects of a telomere destabilizing agent on cancer cell-cycle dynamics--integrated modelling and experiments.
abstract: The pentacyclic acridinium salt RHPS4 displays anti-tumour properties in vitro as well as in vivo and is potentially cell-cycle specific. We have collected experimental data and formulated a compartmental model using ordinary differential equations to investigate how the compound affects cells in each stage of the cell cycle. In addition to a control case in which no drug was used, we treated colorectal cancer cells with three different concentrations of the drug and fitted simulations from our models to experimental observations. We found that RHPS4 caused a concentration-dependent, marked cell death in treated cells, which is best modelled by allowing the rate parameters corresponding to cell death to be sigmoidal functions of time. We have shown that the model is "identifiable", meaning that, at least in principle, the parameter values can be determined from observable quantities. We find that at low concentrations RHPS4 primarily affects the cells in the G(2)/M phase, and that the drug has a delayed effect with the delay decreasing at larger doses. Since the drug diffuses into the nucleus, the observed delayed effect of the compound is unexpected and is a novel finding of our research into this compound.
authors: School of Mathematical Sciences, University of Nottingham, University Park, Nottingham, United Kingdom. pmxbvh@nottingham.ac.uk
authors: Bartholomäus V
authors: BV
authors: Hirt
authors: Jonathan A D
authors: JA
authors: Wattis
authors: Simon P
authors: SP
authors: Preston
authors: Charles A
authors: CA
authors: Laughton
mesh_terms: D000166:Acridines / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004273:DNA, Neoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D045325:HCT116 Cells; D006801:Humans; D008954:Models, Biological; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000187:drug effects
chemical_list: C438609:3,11-difluoro-6,8,13-trimethyl-8H-quino(4,3,2-kl)acridinium; D000166:Acridines; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D019098:Telomerase