Pang Siu-Kwong, Yu Chun-Wing, Au-Yeung Steve C F, Ho Yee-Ping
School of Pharmacy, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
Biochem Biophys Res Commun. 2007 Nov 9;363(1):235-40. doi: 10.1016/j.bbrc.2007.08.172. Epub 2007 Sep 7.
Oxaliplatin is a third generation platinum (Pt) drug with a diaminocyclohexane (DACH) entity, which has recently obtained worldwide approval for the clinical treatment of colon cancer, and apparently operates by a different mechanism of action to the classical cisplatin or carboplatin. Introducing a novel dual mechanism of action is one approach in designing a new platinum-based anticancer agent, whereby an appropriate ligand, such as demethylcantharidin (DMC), is released from the parent compound to exert a cytotoxic effect, in addition to that of the DNA-alkylating function of the platinum moiety. To investigate the likelihood of a novel dual mechanism of anticancer action, demethylcantharidin-integrated Pt complexes: Pt(R,R-DACH)(DMC) with the same Pt-DACH moiety as oxaliplatin, and Pt(NH(3))(2)(DMC) akin to carboplatin; were studied for their ability to induce DNA damage in HCT116 colorectal cancer cells by an alkaline comet assay. The results showed that the DMC ligand released from the novel complexes caused additional DNA lesions when compared with oxaliplatin and carboplatin. The comet assay also revealed that the DNA-damaging behavior of cisplatin is characteristically different; and this study is the first to demonstrate the ability of DMC to induce DNA lesions, thus providing sufficient evidence to explain the superior antiproliferative effect of the novel DMC-integrated complexes.
奥沙利铂是一种带有二氨基环己烷（DACH）基团的第三代铂（Pt）类药物，最近已在全球范围内获批用于结肠癌的临床治疗，其作用机制显然与经典的顺铂或卡铂不同。引入一种新的双重作用机制是设计新型铂类抗癌药物的一种方法，即从母体化合物中释放出一种合适的配体，如去甲斑蝥素（DMC），除了铂部分的DNA烷基化功能外，还能发挥细胞毒性作用。为了研究抗癌作用新的双重机制的可能性，对去甲斑蝥素整合的铂配合物进行了研究：与奥沙利铂具有相同Pt-DACH部分的Pt（R，R-DACH）（DMC），以及类似于卡铂的Pt（NH(3))(2)(DMC）；通过碱性彗星试验研究了它们在HCT116结肠癌细胞中诱导DNA损伤的能力。结果表明，与奥沙利铂和卡铂相比，新型配合物释放的DMC配体导致了额外的DNA损伤。彗星试验还表明顺铂的DNA损伤行为具有特征性差异；并且这项研究首次证明了DMC诱导DNA损伤的能力，从而为解释新型DMC整合配合物的优越抗增殖作用提供了充分的证据。
