BBR 3464: A novel triplatinum complex, exhibiting a preclinical profile ofantitumor efficacy different from cisplatin

Multinuclear platinum complexes represent a new class of anticancer agents, distinct in terms of DNA binding features and the profile of antitumor act ivity from their mononuclear counterparts, in particular cisplatin, Among c omplexes of this class, BBR 3464, a trinuclear platinum compound has been s elected for preclinical development. In the present study, we describe the preclinical evaluation of BBR 3464 in a series of human tumor cell lines an d tumor xenografts, with special emphasis on tumor types known to be resist ant to cisplatin, In a panel of seven human tumor cell lines naturally resi stant to cisplatin (three ovarian and four melanomas), BBR 3464 was extreme ly potent with IC,, values at least 20-fold lower than cisplatin, Against e ight human tumor xenografts including four tumors refractory to cisplatin, BBR 3464 was confirmed to be very active with a tumor weight inhibition >80 % in seven of them. The efficacy of BBR 3464 against cisplatin-resistant tu mors was consistent with the ability of the drug to completely overcome res istance in three cell systems characterized by acquired resistance to cispl atin, Moreover, BBR 3464 caused a more prolonged effect than cisplatin, whi ch was reflected by higher specific growth delay values. This prolonged eff ect is likely to be related to a more persistent perturbation of the cell c ycle induced by BBR 3464 than by cisplatin, as shown in one ovarian tumor c ell line. Finally, the profile of sensitivity to BBR 3364 within the 60-cel l-lines screening panel of the National Cancer Institute, NIH (Bethesda, MD ) differed from those of established drugs, thus supporting the hypothesis of a distinct mechanism of cytotoxic activity of BBR 3464, The novel trinuc lear platinum complex, in light of its innovative antitumor activity profil e, has the potential to become a useful clinical agent for the treatment of unresponsive tumors.