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

Abstract

Summary The anti-tumour activity of CPT-l 1, 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 lp deletions and overexpression of the human mdrl 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-' 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-' day-'). 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.

No topoisomerase I alteration in a neuroblastoma model with in vivo acquired resistance to irinotecan

“…IGR-NB8 xenograft model was derived from a newly diagnosed stage 3 abdominal NB in a 5-year-old boy, by direct subcutaneous transplantation of small tumour fragments into previously irradiated athymic mice (Vassal et al, 1996). The primary tumour of this patient was refractory to conventional chemotherapy that included platinum compounds, cyclophosphamide, doxorubicin, etoposide and vincristine.…”

“…The MDR1 gene was overexpressed. IGR-NB8 proved to be sensitive in vivo to CPT-11, topotecan, cyclophosphamide and cisplatin, but refractory to etoposide (VP16) (Vassal et al, 1996(Vassal et al, , 1997.…”

“…in a caudal vein at a dose of 27 mg kg À1 day À1 for 5 consecutive days. This dose was previously shown to induce 100% complete regressions (CR) and to be well tolerated (no treatment-related death and no body weight loss) (Vassal et al, 1996). This treatment was repeated every 21 days (one cycle) for a maximum of four consecutive cycles (one passage).…”

“…We have previously shown that i.v. treatment with CPT-11 resulted in extensive tumour regression and growth delay in three different NB xenograft models (Vassal et al, 1996). Similarly, Thompson et al (1997b) showed that oral CPT-11 was active against a panel of six NB xenografts.…”

“…CPT-11 has demonstrated antitumour activity against a wide spectrum of both adult and paediatric xenografts in preclinical studies (Komuro et al, 1994;Vassal et al, 1996;Thompson et al, 1997a). We have previously shown that i.v.…”