Mode of action of bredinin with guanylic acid on L5178Y mouse leukemia cells.

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Abstract
Moderate concentrations of bredinin (1.2×10-5 M) strongly inhibited growth of L5178Y cells, with the effect being reversed by guanylic acid (GMP). However, at higher concentrations of bredinin the inhibition was not reversed completely by GMP added in excess. Bredinin was cytocidal at concentrations above 2×10-5 M, but 5×10-5 M bredinin in the presence of excess GMP, bredinin was cytostatic. Bredinin inhibited nucleic acid synthesis of L5178Y cells, but bredinin itself was not incorporated into the nucleic acid. Inhibition of nucleic acid synthesis was clearly reversed by GMP. Similarly chromosomal aberrations in L5178Y cells caused by bredinin were reversed by GMP. In contrast, the effect of a high concentration of bredinin on cell multiplication was not reversed by GMP. The modal volume of L5178Y cells increased during incubation in the presence of bredinin and GMP for 24 hours, 5×10-5 M bredinin with GMP causing a 70% increase in cell volume. This increase in cell volume was mainly due to an increase in the protein content of the cells. The cytostatic effect of bredinin with GMP was reversed completely by adenosine-3', 5'-cyclic monophosphate (cyclic AMP). Other cyclic nucleotides and nucleotides were ineffective. The reversing effect of cyclic AMP on cell survival depended upon the concentration of GMP, and was not seen in the absence of GMP. It was concluded that cyclic AMP influences the secondary cytostatic effect of bredinin, and not the primary cytotoxic effect reversed by GMP.