Genotoxic effects of irinotecan combined with the novel platinum(II) complexes in human cancer cells

Abstract

Combination chemotherapy has become increasingly important as synergistic drugs enable to achieve therapeutic effects at substantially lower doses and limited spectrum of side effects. Irinotecan as a one of the camptothecin analogues has shown a broad spectrum of antitumor activity against various malignancies. It is commonly used in treatment of gastrointestinal and pulmonary cancer. In this study were measured the effect of the novel platinum(II) complexes: cis-[PtCl 2(4-pmOpe) 2] and trans-[PtCl 2(4-pmOpe) 2], with diethyl (pyridine-4-ylmethyl)phosphates (4-pmOpe) as non-leaving ligands, on genotoxicity of irinotecan in human cancer cells. Irinotecan showed genotoxic activity in combination with the new platinum(II) derivatives in cancer cells. Combination of irinotecan with cis-[PtCl 2(4-pmOpe) 2] or trans-[PtCl 2(4-pmOpe) 2] resulted in significant increase in DNA damage in A549 and HT29 cells when compared to effects of irinotecan or platinum(II) complexes used separately. The highest degree of DNA migration in the comet tails was found after the cancer cells were treated with irinotecan and trans-[PtCl 2(4-pmOpe) 2]. In addition, the analysis of DNA repair revealed that irinotecan in combination with trans-[PtCl 2(4-pmOpe) 2] induced unrepairable DNA damage suggesting the poor recognition of the damage by HMG proteins and other repair mechanisms. Thus, genotoxicity of irinotecan was modulated by the structurally different DNA–platinum adducts formed by novel platinum(II) complexes. These data suggest that the use of irinotecan with novel platinum(II) complexes may represent a new strategy for pharmacotherapy in cancer.