Effects of a piperidine ligand on DNA modification by antitumor cisplatin analogues

Abstrakt

Replacement of the ammine group in antitumor cisplatin by a heterocyclic ligand (piperidine, piperazine, or 4-picoline) results in reduction of cytotoxicity in human ovarian cancer cells. DNA is generally believed to be a major pharmacological target of antitumor platinum complexes. Therefore, we examined conformation of oligodeoxyribonucleotide duplexes containing a cross-link of cis-[PtCl2(NH3)(piperidine)], their recognition by high mobility group proteins, and nucleotide excision repair; that is, some of the processes that may mediate antitumor effects of platinum drugs. The replacement does not affect the DNA binding mode including conformational alterations and excision of the cross-links. The results suggest that in certain cancer cells the lower cytotoxicity of cis- [PtCl2(NH3)(piperidine)] might be partially associated with reduced affinity of the high mobility group proteins to the major intrastrand cross-links of this analogue relative to the same adducts of cisplatin. Besides this and a number of other biochemical factors, the reduced intracellular accumulation with subsequent effects on the level of DNA platination in the cells may also contribute to the reduced cytotoxicity of cis-[PtCl2(NH3)(piperidine)]. The results support the view that the concept based on the design of the complexes structurally derived from cisplatin that do not present an altered DNA binding mode may be less effective in the search for new platinum drugs that would overcome cisplatin resistance.