Correlation of in vitro anti-proliferative potential with in vivo teratogenicity in a series of valproate analogues.
The prediction that an anti-proliferative effect coupled with a pro-differentiative action will detect a neural tube teratogen has been validated by comparison of these in vitro endpoints with in vivo teratogenicity in a series of closely allied valproate structural analogues. The majority of the compounds significantly inhibited C6 glioma proliferation, the most potent compounds being ranked as octanoic acid > 2-propylhexanoic acid > or = 2-ethylhexanoic acid > or = valproic acid. The anti-proliferative potency of these compounds did not correlate strictly to their relative in vivo teratogenic potential. Valproic acid exhibited an anti-proliferative IC50 of 1.45 mM, whereas 2-propyl-2-pentenoic acid and 2-propyl-4-pentenoic acid were virtually indistinguishable, exhibiting significantly lower IC50 values of 2.5 and 2.55 mM, respectively. The concanavalin A lectin affinity assay was employed to establish whether an anti-proliferative action was coupled with an increased state of cell differentiation. In this lectin affinity assay, the most potent analogues to significantly attenuate the affinity of exposed C6 glioma cells for concanavalin A lectin-coated plastic included 2-butylhexanoic acid, 2-propyl-4-pentenoic acid, 2-propylhexanoic acid and 2-ethylhexanoic acid in a manner which can be related to their relative teratogenic potencies in vivo. All compounds screened positive in both the anti-proliferative and pro-differentiative assays exhibited in vivo exencephalic rates of 5-44%. These included valproic acid, 2-ethylhexanoic acid, 2-propylhexanoic acid and 2-butylhexanoic acid. It would appear that combined anti-proliferative and pro-differentiative screens provide a promising detection system for teratogenic status in a series of valproate analogues.
Courage-Maguire
C
C
Department of Pharmacology, University College, Belfield, Dublin, Ireland.
Bacon
C L
CL
Nau
H
H
Regan
C M
CM
D000014:Abnormalities, Drug-Induced; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002999:Clone Cells; D051379:Mice; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000031:analogs & derivatives*
D014635:Valproic Acid