C. Manzotti et al., BBR 3464: A novel triplatinum complex, exhibiting a preclinical profile ofantitumor efficacy different from cisplatin, CLIN CANC R, 6(7), 2000, pp. 2626-2634
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.