Busulphan is active against neuroblastoma and medulloblastoma xenografts in athymic mice at clinically achievable plasma drug concentrations

High-dose busulphan-containing chemotherapy regimens have shown high respon se rates in children with relapsed or refractory neuroblastoma, Ewing's sar coma and medulloblastoma. However, the anti-tumour activity of busulfan as a single agent remains to be defined, and this was evaluated in athymic mic e bearing advanced stage subcutaneous paediatric solid tumour xenografts. B ecause busulphan is highly insoluble in water, the use of several Vehicles for enteral and parenteral administration was first investigated in terms o f pharmacokinetics and toxicity. The highest bioavailability was obtained w ith busulphan in DMSO administered i.p. When busulphan was suspended in car boxymethylcellulose and given orally or i.p., the bioavailability was poor. Then, in the therapeutic experiments, busulphan in DMSO was administered i .p. on days 0 and 4. At the maximum tolerated total dose (50 mg kg(-1)), bu sulphan induced a significant tumour growth delay, ranging from 12 to 34 da ys in the three neuroblastomas evaluated and in one out of three medullobla stomas. At a dose level above the maximum tolerated dose, busulphan induced complete and partial tumour regressions. Busulphan was inactive in a perip heral primitive neuroectodermal tumour (PNET) xenograft. When busulphan pha rmacokinetics in mice and humans were considered, the estimated systemic ex posure at the therapeutically active dose in mice (113 mu g h ml(-1)) was c lose to the mean total systemic exposure in children receiving high-dose bu sulphan (102.4 mu g h ml(-1)). In conclusion, busulphan displayed a signifi cant anti-tumour activity in neuroblastoma and medulloblastoma xenografts a t plasma drug concentrations which can be achieved clinically in children r eceiving high-dose busulphan-containing regimens.