THERAPEUTIC ACTIVITY OF CPT-11, A DNA-TOPOISOMERASE-I INHIBITOR, AGAINST PERIPHERAL PRIMITIVE NEUROECTODERMAL TUMOR AND NEUROBLASTOMA XENOGRAFTS

The anti-tumour activity of CPT-11, a topoisomerase I inhibitor, was e valuated in four human neural-crest-derived paediatric tumour xenograf ts: one peripheral primitive neuroectodermal tumour (pPNET) (SK-N-MC) and three neuroblastomas. Two models, SK-N-MC and IGR-N835, were estab lished in athymic mice from a previously established in vitro cell lin e. Two new neuroblastoma xenograft models, IGR-NB3 and IGR-NB8, were d erived from previously untreated non-metastatic neuroblastomas. They e xhibited the classic histological features of immature neuroblastoma a long with N-myc amplification, paradiploidy, chromosome 1p deletions a nd overexpression of the human mdr 1 gene. These tumour markers have b een shown to be poor prognostic factors in children treated for neurob lastoma. CPT-11 was tested against advanced stage subcutaneous tumours . CPT-II was administered i.v. using an intermittent (q4d x 3) and a d aily x 5 schedule. The optimal dosage and schedule was 40 mg kg(-1) da ily for 5 days. At this highest non-toxic dose, CPT-11 induced 100% tu mour-free survivors on day 121 in mice bearing the pPNET SK-N-MC xenog raft. For the three neuroblastoma xenografts, 38-100% complete tumour regressions were observed with a tumour growth delay from 38 to 42 day s, and anti-tumour activity was clearly sustained al a lower dosage (2 7 mg kg(-1) day(-1)). The efficacy of five anti-cancer drugs commonly used in paediatric oncology or in clinical development was evaluated a gainst SK-N-MC and IGR-N835. The sensitivity of these two xenografts t o cyclophosphamide, thiotepa and cisplatin was of the same order of ma gnitude as that of CPT-11, but they were refractory to etoposide and t axol. In conclusion, CPT-II demonstrated significant activity against pPNET and neuroblastoma xenografts. Further clinical development of CP T-11 in paediatric oncology is warranted.