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. 1996 Aug;74(4):537–545. doi: 10.1038/bjc.1996.398

Therapeutic activity of CPT-11, a DNA-topoisomerase I inhibitor, against peripheral primitive neuroectodermal tumour and neuroblastoma xenografts.

G Vassal 1, M J Terrier-Lacombe 1, M C Bissery 1, A M Vénuat 1, F Gyergyay 1, J Bénard 1, J Morizet 1, I Boland 1, P Ardouin 1, B Bressac-de-Paillerets 1, A Gouyette 1
PMCID: PMC2074686  PMID: 8761367

Abstract

The anti-tumour activity of CPT-11, a topoisomerase I inhibitor, was evaluated in four human neural-crest-derived paediatric tumour xenografts; one peripheral primitive neuroectodermal tumour (pPNET) (SK-N-MC) and three neuroblastomas. Two models, SK-N-MC and IGR-N835, were established in athymic mice from a previously established in vitro cell line. Two new neuroblastoma xenograft models, IGR-NB3 and IGR-NB8, were derived from previously untreated non-metastatic neuroblastomas. They exhibited the classic histological features of immature neuroblastoma along with N-myc amplification, paradiploidy, chromosome 1p deletions and overexpression of the human mdr 1 gene. These tumour markers have been shown to be poor prognostic factors in children treated for neuroblastoma. CPT-11 was tested against advanced stage subcutaneous tumours. CPT-11 was administered i.v. using an intermittent (q4d x 3) and a daily x 5 schedule. The optimal dosage and schedule was 40 mg kg-1 daily for 5 days. At this highest non-toxic dose, CPT-11 induced 100% tumour-free survivors on day 121 in mice bearing the pPNET SK-N-MC xenograft. For the three neuroblastoma xenografts, 38-100% complete tumour regressions were observed with a tumour growth delay from 38 to 42 days, and anti-tumour activity was clearly sustained at a lower dosage (27 mg kg-1 day-1). The efficacy of five anti-cancer drugs commonly used in paediatric oncology or in clinical development was evaluated against SK-N-MC and IGR-N835. The sensitivity of these two xenografts to cyclophosphamide, thiotepa and cisplatin was of the same order of magnitude as that of CPT-11, but they were refractory to etoposide and taxol. In conclusion, CPT-11 demonstrated significant activity against pPNET and neuroblastoma xenografts. Further clinical development of CPT-11 in paediatric oncology is warranted.

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Selected References

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