title: Stochastic dynamics of leukemic cells under an intermittent targeted therapy.
abstract: The evolutionary dynamics of cancerous cell populations in a model of Chronic Myeloid Leukemia (CML) is investigated in the presence of an intermittent targeted therapy. Cancer development and progression is modeled by simulating the stochastic evolution of initially healthy cells which can experience genetic mutations and modify their reproductive behavior, becoming leukemic clones. Front line therapy for the treatment of patients affected by CML is based on the administration of tyrosine kinase inhibitors, namely imatinib (Gleevec) or, more recently, dasatinib or nilotinib. Despite the fact that they represent the first example of a successful molecular targeted therapy, the development of resistance to these drugs is observed in a proportion of patients, especially those in advanced stages. In this study, we simulate an imatinib-like treatment of CML by modifying the fitness and the death rate of cancerous cells and describe the several scenarios in the evolutionary dynamics of white blood cells as a consequence of the efficacy of the different modeled therapies. The patient response to the therapy is investigated by simulating a drug administration following a continuous or pulsed time scheduling. A permanent disappearance of leukemic clones is achieved with a continuous therapy. This theoretical behavior is in a good agreement with that observed in previous clinical investigations. However, these findings demonstrate that an intermittent therapy could represent a valid alternative in patients with high risk of toxicity. A suitable tuned pulsed therapy can also reduce the probability of developing resistance.
authors.affiliation: Dipartimento di Fisica, Group of Interdisciplinary Physics, Università di Palermo, Viale delle Scienze, ed. 18, 90128, Palermo, Italy. npizzolato@gip.dft.unipa.it
authors.forename: Nicola
authors.initials: N
authors.lastname: Pizzolato
authors.forename: Dominique
authors.initials: D
authors.lastname: Persano Adorno
authors.forename: Davide
authors.initials: D
authors.lastname: Valenti
authors.forename: Bernardo
authors.initials: B
authors.lastname: Spagnolo
mesh_terms: D001549:Benzamides; D003198:Computer Simulation; D018450:Disease Progression; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D013269:Stochastic Processes
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate