DNA-topoisomerase I is the nuclear target of new anticancer drugs, namely
camptothecin and its derivatives. In order to establish the rational basis for their clinical development in paediatric oncology, the antitumour activity of
irinotecan (CPT-11) and
topotecan, two
camptothecin water-soluble derivatives, was studied in nude mice bearing
neuroblastoma xenografts. The panel was composed of 4 previously established subcutaneous xenograft lines (IGR-N835, IGR-N91, IGR-NB3, IGR-NB8) that exhibited the common
biological markers of poor prognosis in children (MYCN amplification, 1p deletion, paradiploidy and/or MDR1 overexpression).
Irinotecan and
topotecan were administered i.v. or i.p. over 5 consecutive days in animals bearing tumours.
Irinotecan (40 mg/kg/day) induced 20-100% complete regressions with tumour growth delays ranging from 20 to 46 days. Two out of 10 IGR-N91 bearing animals were tumour free more than 120 days
after treatment with the top dose (50 mg/kg/day).
Topotecan (2.7 mg/kg/day) induced 0-67% complete regressions with tumour growth delays ranging from 23 to 50 days. One out of 8 IGR-NB3 bearing mice was tumour free at the end of the experiment. The antitumour activity of both drugs was clearly sustained at a lower dose level.
Topoisomerase I activity was assayed in 15
neuroblastomas, 3
ganglioneuroblastomas and 2 normal adrenal glands, using
a DNA relaxation assay.
Topoisomerase I activity ranged from 69 to 1304 arbitrary units/mg of
protein, and was significantly higher in immature
neuroblastomas than in
ganglioneuroblastomas and adrenal glands. In conclusion,
irinotecan and
topotecan are active against
neuroblastoma xenografts. Their target is expressed in patients' tumour samples. Clinical development of
topoisomerase I inhibitors in children with
neuroblastoma is warranted.