Interactions of the antitumor agents mitoxantrone and bisantrene with deoxyribonucleic acids studied by electron microscopy.

摘要: The interactions of the low cardiotoxic antitumor agents 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9, 10-anthracenedione (mitoxantrone) and 9,10-anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazoyl-2-yl)hydrazone] (bisantrene) with pBR322 PM2 DNA have been examined by electron microscopy. Direct evidence was obtained for intercalative binding both drugs, mitoxantrone causing a 13% average length increase in corresponding to approximately 580 drug molecules per circle at saturation bisantrene an 11% 480 bound circle. Considerations known GC preference non-nearest neighbor drugs inspection sequence suggest that available intercalation sites are occupied additional external electrostatic cationic also occurs. An apparent difference behavior as compared no net supercoiled shown be attributable offsetting compaction due extensive supercoiling molecules. This conclusion confirmed independent experiments covalently closed-circular DNA--both native, negatively relaxed--with calf thymus topoisomerase, using ethidium comparison. Ethidium caused 21.3 +/- 3.6% nicked, open-circular PM2-DNA, or 2100 10,300 base pairs. Mitoxantrone 16.6% nicked PM2-DNA equivalent 1700 Electron microscopic measurements on relaxed progressively increasing proportions (from 1.4:1 14:1 pair) revealed onset formation lacelike networks circles linked together. phenomenon, which is not produced bisantrene, attributed inter-DNA links charged side arms accord previous reports causes severe distortion chromatin. examination interaction six derivatives, two networks, strict structural requirements this phenomenon.