DNA-TOPOISOMERASE-I, A NEW TARGET FOR THE TREATMENT OF NEUROBLASTOMA

DNA-topoisomerase I is the nuclear target of new anticancer drugs, nam ely camptothecin and its derivatives. In order to establish the ration al basis for their clinical development in paediatric oncology, the an titumour activity of irinotecan (CPT-11) and topotecan, two camptothec in water-soluble derivatives, was studied in nude mice bearing neurobl astoma xenografts. The panel was composed of 4 previously established subcutaneous xenograft lines (IGR-N835, IGR-N91, IGR-NB3, IGR-NB8) tha t exhibited the common biological markers of poor prognosis in childre n (MYCN amplification, 1p deletion, paradiploidy and/or MDR1 overexpre ssion). 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 rangi ng from 20 to 46 days. Two out of 10 IGR-N91 bearing animals were tumo ur 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 wi th tumour growth delays ranging from 23 to 50 days. One out of 8 IGR-N B3 bearing mice was tumour free at the end of the experiment. The anti tumour activity of both drugs was clearly sustained at a lower dose le vel. Topoisomerase I activity was assayed in 15 neuroblastomas, 3 gang lioneuroblastomas 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 neuroblastoma s than in ganglioneuroblastomas and adrenal glands. In conclusion, iri notecan and topotecan are active against neuroblastoma xenografts. The ir target is expressed in patients' tumour samples. Clinical developme nt of topoisomerase I inhibitors in children with neuroblastoma is war ranted. (C) 1997 Published by Elsevier Science Ltd.