HYBRID MODEL OF ERYTHROPOIESIS AND LEUKEMIA TREATMENT WITH CYTOSINE ARABINOSIDE

International audienceA hybrid model of cell population dynamics, where cells are discrete elements whose dynamics depend on continuous intracellular and extracellular processes, is developed to simulate the evolution of immature red blood cells in the bone marrow. Cell differentiation, self-renewal or apoptosis are determined by an intracellular network, based on two proteins, Erk and Fas, and described by ordinary differential equations, and by local extracellular regulation performed by Fas- ligand, a protein produced by mature cells whose concentration evolution is represented by a partial differential equation. The model is used to study normal and leukemic red blood cell production (erythropoiesis), and treatment of leukemia. Normal cells are assumed to have a circadian rhythm that influences their cell cycle progression, whereas leukemic cells, are assumed to escape circadian rhythms. We consider a treatment based on periodic administration of Ara-C, an anti-cancer agent targeting cells in DNA synthesis. A detailed pharmacodynamic/pharmacokinetic model of Ara-C is proposed and used to simulate the treatment. Influence of the period of the treatment and the day delivery time on the outcome of the treatment is investigated and stress the relevance of considering chronotherapeutic treatments to treat leukemia

HYBRID MODEL OF ERYTHROPOIESIS AND LEUKEMIA TREATMENT WITH CYTOSINE ARABINOSIDE

International audienceA hybrid model of cell population dynamics, where cells are discrete elements whose dynamics depend on continuous intracellular and extracellular processes, is developed to simulate the evolution of immature red blood cells in the bone marrow. Cell differentiation, self-renewal or apoptosis are determined by an intracellular network, based on two proteins, Erk and Fas, and described by ordinary differential equations, and by local extracellular regulation performed by Fas- ligand, a protein produced by mature cells whose concentration evolution is represented by a partial differential equation. The model is used to study normal and leukemic red blood cell production (erythropoiesis), and treatment of leukemia. Normal cells are assumed to have a circadian rhythm that influences their cell cycle progression, whereas leukemic cells, are assumed to escape circadian rhythms. We consider a treatment based on periodic administration of Ara-C, an anti-cancer agent targeting cells in DNA synthesis. A detailed pharmacodynamic/pharmacokinetic model of Ara-C is proposed and used to simulate the treatment. Influence of the period of the treatment and the day delivery time on the outcome of the treatment is investigated and stress the relevance of considering chronotherapeutic treatments to treat leukemia