RESUMO
Haematological toxicity associated with cancer therapeutics is monitored by changes in blood cell count, and their primary effect is on proliferative progenitors in the bone marrow. Using observations in rat bone marrow and blood, we characterize a mathematical model that comprises cell proliferation and differentiation of the full haematopoietic phylogeny, with interacting feedback loops between lineages in homeostasis as well as following carboplatin exposure. We accurately predicted the temporal dynamics of several mature cell types related to carboplatin-induced bone marrow toxicity and identified novel insights into haematopoiesis. Our model confirms a significant degree of plasticity within bone marrow cells, with the number and type of both early progenitors and circulating cells affecting cell balance, via feedback mechanisms, through fate decisions of the multipotent progenitors. We also demonstrated cross-species translation of our predictions to patients, applying the same core model structure and considering differences in drug-dependent and physiology-dependent parameters.
Assuntos
Medula Óssea/efeitos dos fármacos , Carboplatina/toxicidade , Biologia de Sistemas/métodos , Animais , Diferenciação Celular , Proliferação de Células/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , Homeostase , Humanos , Modelos Teóricos , RatosRESUMO
Balancing antitumor efficacy with toxicity is a significant challenge, and drug-induced myelosuppression is a common dose-limiting toxicity of cancer treatments. Mathematical modeling has proven to be a powerful ally in this field, scaling results from animal models to humans, and designing optimized treatment regimens. Here we outline existing mathematical approaches for studying bone marrow toxicity, identify gaps in current understanding, and make future recommendations to advance this vital field of safety research further.