Synergistic Effect in Culture of Bleomycin‐group Antibiotics and N‐Solanesyl‐N, N’‐bis(3,4‐dimethoxybenzyl)ethylenediamine, a Synthetic Isoprenoid

Like bleomycin and peplomycin, libromycin, a newly developed bleomycin‐group antibiotic, was potentiated 130‐fold against Chinese hamster V79 cells (V79/S) and 47‐fold against its multidrug‐resistant mutant (V79/ADM) by N‐solanesyl‐N, N’‐bis(3,4‐dimethoxybenzyl)ethylenediamine (SDB‐ethylenediamine) at 10 and 3 μg/ml, respectively. But neocarzinostatin, known to cause DNA strand scission as bleomycins do, was potentiated only twofold. This suggests that the high potentiation by SDB‐ethylenediamine is unique to the bleomycin‐group antibiotics. Isobologram analysis revealed that the combined effect of peplomycin and SDB‐ethylenediamine was highly synergistic. SDB‐ethylenediamine did not increase the intracellular accumulation of [(3)H]peplomycin in V79/S cells. Analyses by an alkaline elution method demonstrated that single strand scission in DNA of intact V79/S cells caused by 1‐h incubation with peplomycin was greatly stimulated by pre‐ and co‐existence of SDB‐ethylenediamine, but DNA strand breaks in isolated nuclei were not affected. Apparently some cytoplasmic constituent(s) is involved in the potentiation mechanism. SDB‐ethylenediamine did not block the DNA repair which occurred after the removal of peplomycin from the medium. Two fragments of SDB‐ethylenediamine, solanesol (polyprenoid moiety) and a diamine component (verapamil‐like moiety), were not synergistic with peplomycin, even when they were mixed together. This indicates that the steric conformation of the intact SDB‐ethylenediamine molecule is important for the activity.