Discipline of Biomedical Science, School of Medical Sciences, Sydney Medical School, The University of Sydney, Cumberland Campus C42, 75 East Street, Lidcombe, NSW1825, Australia.
Med Chem. 2011 Nov;7(6):593-8. doi: 10.2174/157340611797928316.
Development of drug resistance and the presence of dose-limiting side-effects remain the two main problems in cancer chemotherapy. Combination of drugs with different mechanisms of action can offer a distinct advantage over monotherapy in overcoming drug resistance and reducing the side-effects. In this study synergism in activity from the combinations of cisplatin (Cis) with two multicentred platinum complexes coded as TH1 and DH6Cl in the human ovarian A2780, A2780cisR and A27800473R cancer cell lines had been investigated. Although Cis, TH1 and DH6Cl all bind with nucleobases in the DNA, they differ in the nature of adducts formed and the non-covalent interactions they may undergo. Whereas Cis binds with nucleobases in the DNA forming mainly intrastrand bifunctional adducts such 1,2-Pt(GG) and 1,2-Pt(AG), TH1 and DH6Cl are expected to form mainly interstrand bifunctional G-Pt.....Pt-G adducts with the DNA. It was found that Cis in combination with TH1 and DH6Cl produced both sequence- and concentration-dependent synergism. Generally greater synergism was produced when the two compounds were added at the same time than with a 4 h time gap. For the combination of Cis with TH1, significant synergism was produced only in the parent A2780 cell line but not in the resistant A2780(cisR) and A2780(0473R) cell lines, thus indicating that the combinations of Cis with TH1 would not offer any advantage in overcoming the drug resistance. In contrast, 0/0 h and 4/0 h combinations of Cis and DH6Cl in A2780(cisR) cell line were found to be synergistic, thus indicating that combinations of Cis with DH6Cl may offer a therapeutic advantage. Although both TH1 and DH6Cl are expected to form a number of long-range interstrand G-Pt......Pt-G adducts with nucleobases in the DNA, TH1 and DHCl are expected to differ in their non-covalent interactions with the DNA due to the presence of two 3-hydroxypyridine ligands bound to the central metal ion in TH1 but not in DH6Cl which instead contains two ammino ligands bound to the central palladium ion.
耐药性的发展和剂量限制副作用的存在仍然是癌症化疗的两个主要问题。与单一药物治疗相比，具有不同作用机制的药物联合使用可以在克服耐药性和减少副作用方面具有明显优势。在这项研究中，研究了 cisplatin（顺铂）（Cis）与两个代号为 TH1 和 DH6Cl 的多中心铂复合物在人卵巢 A2780、A2780cisR 和 A27800473R 癌细胞系中的组合的协同作用。虽然 Cis、TH1 和 DH6Cl 都与 DNA 中的碱基结合，但它们形成的加合物的性质和可能发生的非共价相互作用不同。顺铂与 DNA 中的碱基结合形成主要是链内双功能加合物，如 1,2-Pt(GG)和 1,2-Pt(AG)，而 TH1 和 DH6Cl 预计与 DNA 形成主要是链间双功能 G-Pt.....Pt-G 加合物。结果发现，Cis 与 TH1 和 DH6Cl 联合使用产生了序列和浓度依赖性协同作用。通常，当两种化合物同时添加时，会产生更大的协同作用，而不是相隔 4 小时。对于 Cis 与 TH1 的组合，仅在亲本 A2780 细胞系中产生显著协同作用，而在耐药 A2780(cisR)和 A2780(0473R)细胞系中则没有产生协同作用，因此表明 Cis 与 TH1 的组合不会在克服耐药性方面提供任何优势。相反，在 A2780(cisR)细胞系中，Cis 与 DH6Cl 的 0/0 h 和 4/0 h 组合被发现具有协同作用，因此表明 Cis 与 DH6Cl 的组合可能具有治疗优势。尽管 TH1 和 DH6Cl 都预计与 DNA 中的碱基形成许多长程链间 G-Pt......Pt-G 加合物，但由于 TH1 中存在两个结合在中心金属离子上的 3-羟基吡啶配体，而 DH6Cl 中不存在，因此它们与 DNA 的非共价相互作用预计会有所不同，DH6Cl 中含有两个结合在中心钯离子上的氨基配体。
