A novel trinuclear platinum complex overcomes cisplatin resistance in an osteosarcoma cell system

Multinuclear platinum compounds have been designed to circumvent the cellul ar resistance to conventional platinum-based drugs. In an attempt to examin e the cellular basis of the preclinical antitumor efficacy of a novel multi nuclear platinum compound (BBR 3464) in the treatment of cisplatin-resistan t tumors, we have performed a comparative study of cisplatin and BBR 3464 i n a human osteosarcoma cell line (U2-OS) and in an in vitro selected cispla tin-resistant subline (U2-OS/Pt). A marked increase of cytotoxic potency of BBR 3464 in comparison with cisplatin in U2-OS cells and a complete lack o f cross-resistance in U2-OS/Pt cells were found. A detailed analysis of the cisplatin-resistant phenotype indicated that it was associated with reduce d cisplatin accumulation, reduced interstrand cross-link (ICL) formation an d DNA platination, microsatellite instability, and reduced expression of th e DNA mismatch repair protein PMS2. Despite BBR 3464 charge and molecular s ize, in U2-OS and U2-OS/Pt cells, BBR 3464 accumulation and DNA-bound plati num were much higher than those observed for cisplatin. In contrast, the fr equency of ICLs after exposure to BBR 3464 was very low. The time course of ICL formation after drug removal revealed a low persistence of these types of DNA lesions induced by BBR 3464, in contrast to an increase of DNA lesi ons induced by cisplatin, suggesting that components of the DNA repair path way handle the two types of DNA lesions differently. The cellular response of HCT116 mismatch repair-deficient cells was consistent with a lack of inf luence of mismatch repair status on BBR 3464 cytotoxicity. Because BBR 3464 produces high levels of lesions different from ICLs, likely including intr a-strand cross-links and monoadducts, the ability of the triplatinum comple x to overcome cisplatin resistance appears to be related to a different mec hanism of DNA interaction (formation of different types of drug-induced DNA lesions) as compared with conventional mononuclear complexes rather than t he ability to overcome specific cellular alterations.