title: A compartmental model of mouse thrombopoiesis and erythropoiesis to predict bone marrow toxicity after internal irradiation.
abstract: In targeted radionuclide radiotherapy, the relationship between bone marrow (BM) toxicity and absorbed dose seems to be elusive. A compartmental model of mouse thrombopoiesis and erythropoiesis was set up to predict the depletion of hematopoietic cells as a function of the irradiation dose delivered to BM by injected radiopharmaceuticals. All simulated kinetics were compared with experimental toxicity for several stages of differentiation of the 2 hematopoietic lineages.
  
  
  METHODS
  C57BL/6 mice were injected either with (18)FNa (37 and 60 MBq), a bone-seeking agent, or with saline. BM mean absorbed doses were calculated according to the MIRD formalism from small-animal PET/CT images. Hematologic toxicity was monitored over time, after (18)FNa injection, by studying BM progenitors and precursors in addition to blood cells. The compartmental model takes into account the pharmacokinetics of the compound, in addition to cellular kinetics and cell radiosensitivities for the 2 studied lineages.
  
  
  RESULTS
  Because biodistribution studies showed an uptake of (18)FNa in bones, the skeleton was considered as the principal source organ of BM irradiation. The time-activity curve obtained from validated quantification of PET/CT images allowed for the calculation of mean absorbed doses to the whole BM of 2.1 and 3.4 Gy for (18)FNa injections of 37 and 60 MBq, respectively. Concerning hematologic toxicity, the model was in good agreement for the 2 absorbed doses with experimental measurements of cell depletion for platelets, progenitors, and precursors within the BM in terms of time to nadir, depletion intensity, and time to recovery. The same agreement was obtained for red blood cells and their precursors. Model predictions demonstrated that BM toxicity was in correlation with the mean absorbed dose as higher depletions at nadir and longer delays to recovery were noticed for 3.4 Gy than for 2.1 Gy.
  
  
  CONCLUSIONS
  The developed compartmental model of thrombopoiesis and erythropoiesis in a BM toxicity context, after internal irradiation, allowed for the prediction of cell kinetics of BM progenitors, precursors, and mature blood cells in a dose-dependent manner. This model could therefore be used to predict hematologic toxicity in preclinical internal radiotherapy to study the dose-response relationship.
authors.affiliation: L'UNAM Université, Oniris, AMaROC, Nantes, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sas
authors.affiliation: L'UNAM Université, Oniris, AMaROC, Nantes, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Rousseau
authors.affiliation: L'UNAM Université, Oniris, AMaROC, Nantes, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Nguyen
authors.affiliation: L'UNAM Université, Oniris, AMaROC, Nantes, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Bellec
authors.affiliation: Department of Medical Physics, Skåne University Hospital, Lund, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Larrsson
authors.affiliation: L'UNAM Université, Oniris, AMaROC, Nantes, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Becavin
authors.affiliation: L'UNAM Université, Oniris, AMaROC, Nantes, France Department of Medical Physics, Skåne University Hospital, Lund, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Hindorf
authors.affiliation: L'UNAM Université, Oniris, AMaROC, Nantes, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Abadie
authors.affiliation: L'UNAM Université, Oniris, AMaROC, Nantes, France nicolas.chouin@oniris-nantes.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chouin
authors.affiliation: CRCNA, Inserm, CNRS, Université de Nantes, UMR_S 892, Nantes, France; and Arronax GIP, Saint-Herblain, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Barbet
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000528:radiation effects*; D001854:Bone Marrow Cells / Q000166:cytology / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D004920:Erythropoiesis / Q000528:radiation effects*; D005260:Female; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D011874:Radiometry; D034061:Thrombopoiesis / Q000528:radiation effects*
keywords: bone marrow absorbed dose; compartmental model; hematologic toxicity; radionuclide therapy