Multinuclear
platinum compounds have been designed to circumvent the cellular resistance to conventional
platinum-based drugs. In an attempt to examine the cellular basis of the preclinical antitumor efficacy of a novel multinuclear
platinum compound (
BBR 3464) in the treatment of
cisplatin-resistant
tumors, we have performed a comparative study of
cisplatin and
BBR 3464 in a human
osteosarcoma cell line (U2-OS) and in an in vitro selected
cisplatin-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 of cross-resistance in U2-OS/Pt cells were found. A detailed analysis of the
cisplatin-resistant phenotype indicated that it was associated with reduced
cisplatin accumulation, reduced interstrand cross-link (ICL) formation and
DNA platination,
microsatellite instability, and reduced expression of the DNA mismatch repair
protein PMS2. Despite
BBR 3464 charge and molecular size, in U2-OS and U2-OS/Pt cells,
BBR 3464 accumulation and
DNA-bound
platinum were much higher than those observed for
cisplatin. In contrast, the frequency 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 lesions induced by
cisplatin, suggesting that components of the DNA repair pathway handle the two types of DNA lesions differently. The cellular response of HCT116 mismatch repair-deficient cells was consistent with a lack of influence of mismatch repair status on
BBR 3464 cytotoxicity. Because
BBR 3464 produces high levels of lesions different from ICLs, likely including intra-strand cross-links and monoadducts, the ability of the triplatinum complex to overcome
cisplatin resistance appears to be related to a different mechanism of
DNA interaction (formation of different types of
drug-induced DNA lesions) as compared with conventional mononuclear complexes rather than the ability to overcome specific cellular alterations.