Analysis of resonance chemotherapy in leukemia treatment via multi-staged population balance models

• Published in: Journal of theoretical biology 2006-06, Vol.240 (4), p.648-661
• Main Authors: Sherer, E., Hannemann, R.E., Rundell, A., Ramkrishna, D.
• Format: Article
• Language: English
• Subjects: Age-structure; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents, Phytogenic - pharmacology; Camptothecin - administration & dosage; Camptothecin - pharmacology; Cell cycle; Cell Cycle - drug effects; Cell Death - drug effects; Cell Division - drug effects; Coculture Techniques; Drug Administration Schedule; Half-Life; HL-60 Cells; Humans; Jurkat Cells; Leukemia - pathology; Mathematical modeling; Models, Biological
• ISSN: 0022-5193; 1095-8541
• DOI: 10.1016/j.jtbi.2005.11.017

An age-structured population balance model that explicitly models cell cycle phases is developed to investigate the effects of cell cycle specific (CCS) drugs. In particular, the benefits of timing CCS drug treatments in resonance chemotherapy are predicted and measured directly in vitro before evaluating likely in vivo scenarios. The phase transition rates are measured in vitro for the HL60 leukemia cell line and are used to predict the transient phase dynamics after exposure to the S phase specific drug, camptothecin. The phase oscillations predicted by the model are observed experimentally and the timing of a second camptothecin pulse is shown to significantly alter the overall treatment effectiveness. To explore the feasibility of designing resonance chemotherapeutic treatments to preferentially eliminate one cell type over another, Jurkat and HL60 leukemia cells are exposed to the same dual-pulse camptothecin treatment regimen. With the model framework validated for simplified cases, the model is used to extrapolate the effectiveness of resonance chemotherapy considering in vivo effects such as quiescence, drug metabolism, drug properties, and transport considerations that were not included in the in vitro experiments. While resonance chemotherapy is intuitive and looks promising in vitro, when in vivo considerations are included in the model, the phenomenon is dampened and the window of applicability becomes narrower.