The novel trinuclear platinum complex BBR3464 induces a cellular response different from cisplatin

BBR3464 is a new platinum-based drug non cross-resistant with cisplatin. To characterise the cellular basis of BBR3464 cytotoxicity as opposed to cisp latin, we performed a comparative study of the two drugs in cisplatin-resis tant neuroblastoma and astrocytoma cells. In both model systems, BBR3464 pr oved to be more potent than cisplatin and was able to overcome cisplatin re sistance. The higher potency exhibited by BBR3464 correlated with an increa sed cellular platinum accumulation and DNA-adduct formation. At equitoxic d oses, BBR3464 induced apoptosis to a lesser extent than cisplatin and faile d to overcome the decreased susceptibility to cisplatin-induced apoptosis i n cisplatin-resistant cells. Cell cycle analysis showed a dose-dependent G( 2)/M arrest by BBR3464. In astrocytoma cells, cisplatin treatment resulted in the upregulation of p53, p21 and bar. while only p21 induction was obser ved after BBR3464 treatment. In cisplatin-resistant cells, the reduced sens itivity to cisplatin paralleled a resistance to the induction of p53/p21 pa thway by cisplatin, while the same doses of BBR3464 induced p21 to a simila r extent in the resistant cells as in the parental cells. In conclusion, BB R3464 induces a cellular response that is different from cisplatin. support ing the view that the two drugs act through different mechanisms. Our data indicate that BBR3464 may be a promising agent in the treatment of tumours unresponsive to cisplatin and with a non-functional p53. (C) 2001 Elsevier Science Ltd. All rights reserved.