REEVALUATION OF INTERACTION OF CIS-DICHLORO(ETHYLENEDIAMINE)PLATINUM(II) WITH DNA
REEVALUATION OF INTERACTION OF CIS-DICHLORO(ETHYLENEDIAMINE)PLATINUM(II) WITH DNA
复制标题
DOI：
10.1021/bi00361a026
复制
发表时间：
1986-07-01
期刊：
影响因子：
2.9
通讯作者：
EASTMAN, A
中科院分区：
文献类型：
--
作者：
EASTMAN, A
链内交联代表了与癌症化疗药物顺式二氨二氯铂（II）（cis-DDP）相互作用引起的DNA修饰的大部分。这些加合物的特点，虽然最近仍有待解决的几个差异。在这些研究中，使用[3 H]-顺式-二氯（乙二胺）铂（II）（cis-DEP），因为放射性标记方便;这种类似物在DNA中与cis-DDP相同的位点产生加合物。两种药物铂化DNA中的以下序列：GG，65%; AG，25%; GNG，6%。AG序列处的加合物在二聚体的5“-末端上总是具有腺嘌呤。本酶消化方案包括P1核酸酶，其产生完全消化，而不是如先前报道的。在GG处的铂化频率太高，不能用在任何鸟嘌呤处的初始单功能铂化来解释。然而，直接双功能攻击优先在GG被排除，因为单功能加合物可以在短时间内被捕获硫脲。经过短暂的孵育，与顺式DEP和未反应的药物的去除，单官能加合物慢慢重排双官能加合物。有人认为，这种加合物的演变可能是由于药物沿着双螺旋沿着“行走”，这种现象似乎不会发生在单链DNA中。
Intrastrand cross-links represent the majority of modifications in DNA resulting from interaction with the cancer chemotherapeutic drug cis-diamminedichloroplatinum(II) (cis-DDP). These adducts were recently characterized although several discrepancies remained to be resolved. In these studies, [3H]-cis-dichloro(ethylenediamine)platinum(II) (cis-DEP) was used because of the convenience of the radiolabel; this analogue produces adducts at identical sites in DNA as cis-DDP. Both drugs platinate the following sequences in DNA: GG, 65%; AG, 25%; GNG, 6%. The adduct at AG sequences invariably has adenine on the 5''-terminus of the dimer. The present enzyme digestion protocol included P1 nuclease, which produced complete digestion rather than as previously reported. The frequency of platination at GG was too high to be explained by an initial monofunctional platination at any guanine. However, direct bifunctional attack preferentially at GG was obviated because monofunctional adducts could be trapped with thiourea at short time periods. After short incubations, with cis-DEP and removal of unreacted drug, the monofunctional adducts slowly rearranged to bifunctional adducts. It is suggested that this evolution of adducts may result from the drug "walking" along the double helix, a phenomenon that does not appear to occur in single-stranded DNA.