Primary lymphocytes as predictors for species differences in cytotoxic drug sensitivity.
Several in vitro methods have been suggested to predict drug-induced haematotoxicity and species differences; the most commonly used being the clonogenic CFU-GM assay. The aim of the current study was to evaluate whether primary lymphocytes from peripheral blood, assayed with a short-term non-clonogenic assay, could be used to detect species differences in drug sensitivity, and offer an alternative to the CFU-GM assay. The effect of 17 different cytotoxic drugs on lymphocytes from human, dog, rat and mouse was evaluated. A higher sensitivity of human than mouse lymphocytes was seen for topotecan and for 3 of 5 antimetabolites tested. Clear species specificity was also seen for the proteasome inhibitor bortezomib where rodent cells were 50-300 times less sensitive than human cells. Good agreement between our data and published CFU-GM data was observed, suggesting that primary lymphocytes may be a useful model for species difference screening in drug development.
Hassan
S B
SB
Division of Clinical Pharmacology, Department of Medical Sciences, University Hospital, SE-751 85 Uppsala, Sweden. sadia.hassan@medsci.uu.se
Haglund
C
C
Aleskog
A
A
Larsson
R
R
Lindhagen
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004285:Dogs; D005260:Female; D005470:Fluorometry; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D018675:Toxicity Tests / Q000379:methods
D000970:Antineoplastic Agents