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

Abstract：

:High-dose busulphan-containing chemotherapy regimens have shown high response rates in children with relapsed or refractory neuroblastoma, Ewing's sarcoma and medulloblastoma. However, the anti-tumour activity of busulfan as a single agent remains to be defined, and this was evaluated in athymic mice bearing advanced stage subcutaneous paediatric solid tumour xenografts. Because busulphan is highly insoluble in water, the use of several vehicles for enteral and parenteral administration was first investigated in terms of pharmacokinetics and toxicity. The highest bioavailability was obtained with busulphan in DMSO administered i.p. When busulphan was suspended in carboxymethylcellulose 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)), busulphan induced a significant tumour growth delay, ranging from 12 to 34 days in the three neuroblastomas evaluated and in one out of three medulloblastomas. At a dose level above the maximum tolerated dose, busulphan induced complete and partial tumour regressions. Busulphan was inactive in a peripheral primitive neuroectodermal tumour (PNET) xenograft. When busulphan pharmacokinetics in mice and humans were considered, the estimated systemic exposure at the therapeutically active dose in mice (113 microg h ml(-1)) was close to the mean total systemic exposure in children receiving high-dose busulphan (102.4 microg h ml(-1)). In conclusion, busulphan displayed a significant anti-tumour activity in neuroblastoma and medulloblastoma xenografts at plasma drug concentrations which can be achieved clinically in children receiving high-dose busulphan-containing regimens.

journal_name

Br J Cancer

journal_title

British journal of cancer

authors

Boland I,Vassal G,Morizet J,Terrier-Lacombe MJ,Valteau-Couanet D,Kalifa C,Hartmann O,Gouyette A

doi

10.1038/sj.bjc.6690126

subject

Has Abstract

pub_date

1999-02-01 00:00:00

pages

787-92

issue

5-6

eissn

0007-0920

issn

1532-1827

journal_volume

pub_type

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