[The mechanism of a new anthracycline antitumor agent: 1,4-bis [2-(2,2-dimethyl-oxazolidin-3-yl)ethylamino]-1,4-didehydroxy-eta pyrromycinone(AD-89)].
Agarose gel electrophoresis and spectroscopy were used to investigate the interaction of AD-89 with DNA. The effect of drug on intact cell DNA was evaluated by using alkaline elution technique. The results showed that AD-89 decreased the mobility of supercoiled PUC9 DNA significantly. The interaction of calf thymus DNA with AD-89 led to the red shift of the peaks of absorption, and the greater the ratio of DNA/AD-89 was the greater the red shift would be. These results are similar to those of mitoxantrone (DHAQ) and thus suggest that AD-89 is an intercalator. The results of alkaline elution showed that AD-89 produced single-strand breaks at high dose. In contrast to DHAQ, AD-89 did not produce protein-associated breaks. AD-89 produced significantly DNA interstrand cross-linking at 5 and 10 mumol/ L. It also produced DNA protein crosslinks. These results demonstrate that AD-89 is an intercalator and can produce DNA interstrand cross-linking.
Liu
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Department of Pharmacology, School of Basic Medical Sciences, Chengdu.
Bao
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D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D018922:HL-60 Cells / Q000187:drug effects; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology*; D010080:Oxazoles / Q000494:pharmacology*
C110141:1,4-bis(2-(2,2-dimethyloxazolidin-3-yl)ethylamino)-1,4-didehydroxypyrromycinone; D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D007364:Intercalating Agents; D010080:Oxazoles