In vitro and in vivo antitumor activity of the novel trinuclear platinum complex BBR 3464 in neuroblastoma

Purpose: BBR 3463 is a promising new trinuclear platinum complex that has b een shown to circumvent the resistance to cisplatin in a panel of tumor cel l lines and xenografts with acquired or intrinsic resistance to cisplatin. The in vitro and in vivo antitumor activity of BBR 3364 was evaluated and c ompared with that of cisplatin in neuroblastoma. Method's: In in vitro stud ies, the short- and long-term cytotoxicities, cell cycle perturbations, the ability to induce apoptosis. the intracellular platinum accumulation and D NA platination were evaluated in three neuroblastoma cell lines exposed to appropriate drug concentrations for 1 h. In in vivo studies, BBR 3464 was a dministered i.v. at doses of 0.30 and 0.35 mg/kg three times at intervals o f 4 days (q4dx3), and cisplatin was administered i.v. according to two diff erent schedules (at 2 and 4 mg/kg three times at intervals of 4 days and at 6 and 12 mg/kg as single doses). Results: In a short-term growth inhibitio n assay, BBR 3464 was shown to be up to 100-fold more potent than cisplatin and it was even more potent in a clonogenic assay. The difference in the a ntitumor effect of BBR 3464 on the different cell lines was evident in both assays, while cisplatin exerted a comparable antitumor activity in all lin es tested. Cell cycle analysis demonstrated a longer-lasting block in G(2)/ M phase induced by BBR 3464 without the early S phase accumulation induced by cisplatin. The higher potency of BBR 3464 appeared to be unrelated to th e induction of apoptosis, that was lower or at most comparable to cisplatin . Cellular platinum accumulation and platinum-DNA adduct formation followin g BBR 3464 exposure was higher than following cisplatin exposure. These dif ferences may have resulted from a different mechanism of action and may exp lain the lack of cross-resistance with cisplatin. In xenografts of neurobla stoma, BBR 3464 was confirmed to be very potent as compared to cisplatin (M TD 0.35 mg/kg and 4 mg/kg for BBR 3464 and cisplatin, respectively). The ef ficacy of BBR 3464 was superior to that of cisplatin when both drugs were a dministered on a fractionated schedule (q4dx3), while BBR 3463 appeared equ ally active to 12 mg/kg cisplatin administered as a single dose. Conclusion s: Our findings indicate that BBR 3463 has a definite antitumor effect in n euroblastoma lines and map be a candidate for early clinical trials in chil dren with neuroblastoma.