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 micrograms/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 [3H]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.
Institute of Applied Microbiology, University of Tokyo.
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Tomida
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Suzuki
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000031:analogs & derivatives; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D004249:DNA Damage; D004357:Drug Synergism; D005029:Ethylenediamines / Q000494:pharmacology*; D066298:In Vitro Techniques; D017663:Peplomycin; D013729:Terpenes / Q000494:pharmacology*; D009353:Zinostatin / Q000494:pharmacology
D000970:Antineoplastic Agents; D005029:Ethylenediamines; D013729:Terpenes; C048678:N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine; D001761:Bleomycin; D017663:Peplomycin; C054113:liblomycin; D009353:Zinostatin