Effects of CPT‐11 (a unique DNA topoisomerase I inhibitor) on a highly malignant xeno‐transplanted neuroblastoma

Abstract

Although many advances have been made in the management of neuroblastoma, the prognosis of patients with advanced neuroblastoma remains poor, and constant efforts are being made to search for newer effective drugs. CPT-11 is a newly developed derivative of camptothecin and shows a unique anti-tumor activity by inhibiting DNA topoisomerase I. In this study the effects of CPT-11 on a human neuroblastoma xenograft, TNB9, were investigated according to the standard Battelle Columbus Laboratories protocol. TNB9 is one of the most malignant strains of neuroblastoma, showing a homogeneously staining resion (HSR) on chromosome 20 and 80-fold amplification of the N-myc gene. This study disclosed that CPT-11 was highly effective against TNB9. Maximum inhibition rate (IR) was 72.5% at a standard dose and 52.8% even at half the dose. No nude mouse used in this study lost weight after an administration of CPT-11. Plasma pharmacokinetics of CPT-11 administered in this experimental model were compared to that in clinical patients. Our data suggested that CPT-11 might be a promising new drug in the treatment of high-risk neuroblastoma patients and encouraged us to employ CPT-11 in the protocol of the Study Group of Japan.

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

“…CPT-1 1 is clearly active against neuroblastoma and pPNET xenografts, as its anti-tumour activity was retained at doses lower than the optimal dosage. These results are in good agreement with those of Komuro et al (1994) who showed that CPT-11, administered i.p., induced significant tumour growth inhibition in the TNB9 neuroblastoma xenograft model, although no complete tumour regression was reported. CPT-11 was also found to be active against other paediatric cancer (Vassal et al, 1994).…”

Pleiotrophin, a candidate gene for poor tumor vasculature and in vivo neuroblastoma sensitivity to irinotecan

“…CPT-11 a semisynthetic water-soluble analog of camptothecin, is a DNA-topoisomerase I inhibitor and has demonstrated antitumor activity against a wide spectrum of both adult and pediatric xenografts in preclinical studies (Komuro et al, 1994;Vassal et al, 1996;Thompson et al, 1997a). We have previously shown that intravenous (i.v) treatment with CPT-11 resulted in extensive tumor regression and growth delay in three different NB xenograft models (Vassal et al, 1996).…”

Camptothecin Analogs (Irinotecan or Topotecan) plus High-Dose Cyclophosphamide as Preparative Regimens for Antibody-Based Immunotherapy in Resistant Neuroblastoma

“…First, they have impressive activity against NB cell lines resistant to standard anti-NB agents (1)(2)(3)(4)(5); this finding implies that they may provide a novel non-cross-resistant chemotherapeutic addition to the standard drug armamentarium for NB. Second, their nonhematological toxicity (mucositis/topotecan, Refs.…”