Studies on combinations of platinum with paclitaxel and colchicine in ovarian cancer cell lines

Abstract

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).

Conclusion: 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.