Relevance of In Vitro Studies of Drug-Induced Agranulocytosis

Abstract

Bone marrow colony forming unit-granulocyte macrophage (CFU-GM) cultures of 14 patients after neutrophil recovery from drug-induced agranulocytosis (median 12 weeks) were performed in the presence of 20 different drugs and/or acute-phase serum (APS) obtained during agranulocytosis. In 10 cases, drugs involved in agranulocytosis in vivo caused a significant inhibition of CFU-GM growth in vitro in comparison with normal cultures without drug. Three types of direct toxicity are suggested: (i) a decrease in the rate of mitosis; (ii) a destruction of cells (cytotoxic effect); or (iii) a blockage in progenitor mitosis (cytostatic effect). A humoral mechanism was suggested in 1 case because of enhanced inhibition with APS. In 4 cases no effect of the suspected drug could be detected by in vitro studies, but all hypotheses have not been tested in these cases, particularly the possible role of APS and other substances.

A cellular model for drug interactions on hematopoiesis: The use of human umbilical cord blood progenitors as a model for the study of drug-related myelosuppression of normal hematopoiesis

“…Two of these had to be discarded owing to poor clonogenicity. The mean__+ SEM CFU-GM colonies for 200 000 mononuclear cells of BM samples was 58.5___2.8 in our laboratory (Parent-Massin et al, 1993).…”

“…Therefore, assays on reproducibility and the possibility of studying mechanistic aspects are restricted (Kelton et al, 1979;Horikoshi and Murphy, 1982;Okunewick et al, 1985;Ganser et al, 1989;De Lin et al, 1990;Kurtzberg and Carter, 1990;Lemoli and Gulati, 1990;Tohda et al, 1990;Caldwell, 1992;Deldar and Stevens, 1993;Volpe et al, 1993). Nevertheless, bone marrow remains a useful reference method, especially for retrospective patient studies, for example when exploring a humoral or immunotoxic process (Parent-Massin et al, 1993). Sampling of HCB is less invasive and gives a convenient source of normal human hematopoietic progenitors.…”

Evolving Role of Pharmacogenetic Biomarkers to Predict Drug-Induced Hematological Disorders

“…81,82 Bone marrow-derived cells from individuals with agranulocytosis exhibited reduced growth in vitro compared with those from individuals without agranulocytosis. 83 However, no pharmacogenetic markers have been described that specifically predict dapsone-induced agranulocytosis.…”

CFU‐GM Assay for Evaluation of Drug Myelotoxic Activity

“…Since hematotoxicity can result from either the direct interference of the toxicant with the different hematopoietic progenitors or with the expression of cytokines and their receptors, many different protocols have been developed (Naughton et al, 1992;Noble and Sina, 1993;Parent-Massin et al, 1993;San Roman et al, 1994;Parent-Massin and Thouvenot, 1995;Schoeters et al, 1995;Gribaldo et al, 1996Gribaldo et al, , 1998Lewis et al, 1996;Van Den Heuvel et al, 1997;Pessina, 1998;Pessina et al, 1999) and proposed for in vitro hematotoxicity testing, based on the modification of the original technique suggested by Bradley and Metcalf (1966).…”