Abstract

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 A2780cisR and A27800473R 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 A2780cisR 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.

Keywords: Ovarian cancer, drug combination, cisplatin, TH1, DH6Cl, synergism, cancer chemotherapy, drug resistance, DNA forming