[Contribution of in vitro models to the management of hematologic risk in pharmacovigilance].
The decisions of health authorities concerning adverse effects of drugs are usually notified following clinical observations, but are rarely associated to experimental data. The haematopoietic tissue is one of the most sensitive to these effects. In order to anticipate and to explain adverse effects, it becomes necessary to carry out in vitro assays on normal human haematopoietic progenitors. We had the opportunity to use human cord blood progenitors which are able to repopulate allogeneic aplastic bone marrow. Many advantages are associated with this model: numerous samples, non-invasive, absence of species bias, possibilities of mechanistic approach. The clonogenic potential of progenitors in soft agar, as well as their ability to expand in liquid medium after stimulation with specific growth factors, have been used. Evidence of dose-related toxicity by inhibition of colony formation or proliferation was analysed in the presence of reference molecules. Results were reproducible despite an intrinsic variability of progenitor density between samples. They were comparable to assays on bone marrow progenitors reported by us and others. Comparison of toxicity thresholds with plasma therapeutic ranges showed the potential risk for some molecules tested.
Carlhant
D
D
Centre Régional de Pharmacovigilance, Faculté de Médécine, Brest, France.
de Tailly
P D
PD
Vignot
J L
JL
Riché
C
C
Léglise
M C
MC
D000818:Animals; D001773:Blood Cells / Q000187:drug effects*; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D064420:Drug-Related Side Effects and Adverse Reactions; D005312:Fetal Blood / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008954:Models, Biological; D012307:Risk Factors