Eastman A
Biochemistry. 1986 Jul 1;25(13):3912-5. doi: 10.1021/bi00361a026.
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.
链内交联是与癌症化疗药物顺二氨二氯铂（II）（顺铂）相互作用导致的DNA修饰的主要形式。尽管仍有一些差异有待解决，但这些加合物最近已得到表征。在这些研究中，使用了[3H]-顺二氯（乙二胺）铂（II）（顺式DEP），因为放射性标记很方便；这种类似物在DNA中的相同位点产生加合物，与顺铂相同。两种药物在DNA中使以下序列铂化：GG，65%；AG，25%；GNG，6%。AG序列处的加合物在二聚体的5'-末端总是腺嘌呤。目前的酶消化方案包括P1核酸酶，它产生了完全消化，而不是像以前报道的那样。GG处的铂化频率太高，无法用任何鸟嘌呤处的初始单功能铂化来解释。然而，由于单功能加合物可以在短时间内被硫脲捕获，因此避免了优先在GG处的直接双功能攻击。在与顺式DEP短时间孵育并去除未反应的药物后，单功能加合物缓慢重排为双功能加合物。有人认为，这种加合物的演变可能是由于药物沿着双螺旋“移动”，这种现象似乎不会在单链DNA中发生。
