University of Sydney, Lidcombe, Sydney, NSW, Australia.
Anticancer Res. 2010 Oct;30(10):4025-37.
Ovarian cancer remains an ongoing challenge because of the occurrence of resistant forms of tumour for which the drugs fail to function. Combination therapy using drugs with different mechanisms of action offer a means of overcoming drug resistance and reducing the side-effects. In this study, binary combinations of four platinum compounds cisplatin (Cs), oxaliplatin (Ox), YH12 [trans-PtCl(2)(ammino) {imidazo-(1,2-α)pyridine}] and TH1 [{trans-PtCl(NH(3))(2)}(2) {trans-Pt(3-hydroxypyridine)(2)(H(2)N(CH(2)) 6NH(2))(2)}Cl(4)] and two plant-based mitotic inhibitors paclitaxel (Tx) and colchicine (Co) have been used against ovarian cancer cell lines A2780 and A2780(cisR) using five different sequences of addition: 0/0 h, 4/0 h, 0/4 h, 24/0 h and 0/24 h. The strongest synergistic effect was observed when the plant compound (Tx or Co) was added first followed by platinum four hours later with combination index at 50% effect level (fa= 0.5) ranging from 0.03 to 0.36 and 0.10 to 0.72 in A2780 and A2780(cisR) cells respectively. Of all the platinum compounds, Cs showed the greatest synergism when combined with Tx and Co (combination index, CI(50)=0.03 in A2780 and from 0.10 to 0.12 in A2780(cisR)). With the sequence 24/0 h, platinum compounds showed greater synergistic effect with Co than Tx in A2780(cisR). With the sequences 0/4 h and 0/24 h, most of the combinations showed weak synergism to antagonism, especially in A2780(cisR). Antagonism was also observed when the two compounds were added simultaneously, especially in A2780(cisR).
Binary combinations of platinum compounds Cs, Ox, YH12 and TH1 with plant compounds Tx and Co applied to ovarian cancer cell lines showed sequence- and concentration-dependent synergism. The results may have profound implications in therapy, if found to be true in vivo.
卵巢癌仍然是一个持续存在的挑战，因为肿瘤会出现耐药形式，而药物对此无法发挥作用。使用具有不同作用机制的药物进行联合治疗，提供了克服耐药性和减少副作用的方法。在这项研究中，我们使用了四种铂化合物顺铂（Cs）、奥沙利铂（Ox）、YH12[顺式-PtCl2（氨）{咪唑-（1,2-α）吡啶}]和 TH1[{顺式-PtCl（NH3）（2）}{反式-Pt（3-羟基吡啶）（2）（H2N（CH2）6NH2）（2）}Cl4]与两种植物来源的有丝分裂抑制剂紫杉醇（Tx）和秋水仙碱（Co），针对卵巢癌细胞系 A2780 和 A2780（cisR），采用了五种不同的添加顺序：0/0 h、4/0 h、0/4 h、24/0 h 和 0/24 h。当首先添加植物化合物（Tx 或 Co），然后四个小时后添加铂时，观察到最强的协同作用，在 50%效应水平（fa=0.5）的组合指数范围为 0.03 至 0.36 和 0.10 至 0.72，分别在 A2780 和 A2780（cisR）细胞中。在所有铂化合物中，Cs 与 Tx 和 Co 联合使用时显示出最大的协同作用（组合指数，CI50=0.03 在 A2780 中，A2780（cisR）中从 0.10 到 0.12）。对于序列 24/0 h，与 Tx 相比，铂化合物与 Co 的协同作用在 A2780（cisR）中更大。对于序列 0/4 h 和 0/24 h，大多数组合表现出弱协同作用至拮抗作用，尤其是在 A2780（cisR）中。当同时添加这两种化合物时，也观察到拮抗作用，尤其是在 A2780（cisR）中。
顺铂（Cs）、奥沙利铂（Ox）、YH12 和 TH1 与植物化合物 Tx 和 Co 的二元组合，应用于卵巢癌细胞系，表现出序列和浓度依赖性协同作用。如果在体内得到证实，这些结果可能对治疗具有深远的意义。
