新蒽环类抗肿瘤化合物AD─89对DNA的作用机理研究

The Mechanism of a New Anthracycline Antitumor Agent:1,4 bis 2 (2,2 Dimethyl oxazolidin 3 yl)ethylamino 1, 4 didehydroxy η pyrromycinone(AD 89)

采用琼脂糖电泳、紫外光谱法及碱性洗脱法研究新蒽环类抗肿瘤化合物ＡＤ－８９对细胞内外ＤＮＡ的作用，以了解其抗肿瘤作用机理。结果发现：ＡＤ－８９能明显抑制肿瘤细胞生长，减慢超螺旋的ＰＵＣ９ＤＮＡ的电泳迁移率；小牛胸腺ＤＮＡ与ＡＤ－８９作用后可使ＡＤ－８９的紫外吸收峰出现明显红移，提示ＡＤ－８９能嵌入ＤＮＡ；ＡＤ－８９在大剂量时能引起ＤＮＡ单链断裂，但不引起蛋白相关的ＤＮＡ单链断裂，而在５μｍｏｌ／Ｌ和１０μｍｏｌ／Ｌ浓度时均可引起明显的ＤＮＡ链间交叉联接，同时还可引起少量ＤＮＡ－蛋白交联。由此表明，ＡＤ－８９可能是一个主要通过引起细胞内ＤＮＡ链间交联而发挥抗肿瘤作用的嵌入剂。

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 mito xantrone (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 10μmol/L.It also produced DNA protein crosslinks.These results demonstrate that AD 89 is an intercalator and can produce DNA interstrand cross linking.