Synergism from combination of cisplatin and a trans-platinum compound in ovarian cancer cell lines

Development of drug resistance and the presence of dose-limiting side-effects remain two major problems in cancer chemotherapy. Combination of drugs can offer a means of overcoming drug resistance and reducing side-effects. This study investigated synergism in activity from the combinations of cisplatin (Cis) and trans-planaramineplatinum(II) compound YH12 in the human ovarian A2780, A2780(cisR) and A2780(0473R) cancer cell lines. It was found that Cis and YH12 in combination produced both sequence- and concentration-dependent synergism. Addition of Cis first followed by YH12 4 h later produced least synergistic outcomes in all the three cell lines whereas the addition of YH12 first followed by Cis 4 h later and the bolus addition produced much greater synergism. It is believed that as Cis binds with a DNA strand forming intrastrand bifunctional 1,2-Pt(GG) and 1,2-Pt(AG) adducts, the DNA strand is bent. As a result, the subsequent interstrand bifunctional binding of YH12 to the bent DNA would be hampered due to a greater distance mismatch between the two trans-arms of YH12 and the distance between 1,2-interstrand N7(G) and N7(G) positions especially those close to the cisplatin-binding site. This may explain why the 0/4 h addition would be least synergistic in outcome. Conversely, although the interstrand GG binding of YH12 first (that would occur in the 4/0 h and 0/0 h additions), brings about global changes in DNA conformation, it will not significantly affect the subsequent intrastrand bifunctional binding of Cis, so that these modes of addition would result in greater synergistic outcomes. The results of the present study will have implications in the design of combination therapy if confirmed in vivo.