Inhibition of human lymphocyte transformation by the macrocyclic trichothecenes roridin A and verrucarin A

Abstract

The effect of in vitro exposure to the macrocyclic trichothecenes roridin A and verrucarin A on human lymphocyte transformation was evaluated in the mitogen-induced blastogenesis assay. Both compounds were capable of inhibiting stimulation of B- and T-cell subsets by a mitogen panel that included leukoagglutinin, concanavalin A, and pokeweed mitogen. Doses of roridin A and verrucarin A which inhibited [3H]thymidine uptake by 50%, as averaged from this mitogen panel, were 20 and 9 pg/ml, respectively. Verrucarol, a compound which results from base hydrolysis of macrocyclic trichothecenes, had no effect on blastogenesis at levels up to 5 X 10(5) pg/ml, indicating that an intact macrocyclic ring was essential for the potent inhibitory activity of roridin A and verrucarin A. The toxicity of these two compounds was extraordinary relative to that reported for non-macrocyclic trichothecenes and could not be predicted quantitatively from previous structure-activity studies on the toxic and biochemical properties of the trichothecenes.