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

Br J Cancer. 2004 Sep 13;91(6):1205-12. doi: 10.1038/sj.bjc.6602079.

Abstract

CPT-11 (irinotecan) is a DNA-topoisomerase I inhibitor with preclinical activity against neuroblastoma (NB) xenografts. The aim was to establish in vivo an NB xenograft resistant to CPT-11 in order to study the resistance mechanisms acquired in a therapeutic setting. IGR-NB8 is an immature NB xenograft with MYCN amplification and 1p deletion, which is sensitive to CPT-11. Athymic mice bearing advanced-stage subcutaneous tumours were treated with CPT-11 (27 mg kg(-1) day(-1) x 5) every 21 days (1 cycle) for a maximum of four cycles. After tumour regrowth, a new in vivo passage was performed and the CPT-11 treatment was repeated. After the third passage, a resistant xenograft was obtained (IGRNB8-R). The tumour growth delay (TGD) was reduced from 115 at passage 1 to 40 at passage 4 and no complete or partial regression was observed. After further exposure to the drug, up to 28 passages, the resistant xenograft was definitively established with a TGD from 17 at passage 28. Resistant tumours reverted to sensitive tumours after 15 passages without treatment. IGR-NB8-R remained sensitive to cyclophosphamide and cisplatin and cross-resistance was observed with the topoisomerase I inhibitor topotecan. No quantitative or qualitative topoisomerase I modifications were observed. The level of expression of multidrug resistance 1 (MDR1), MDR-associated protein 1 (MRP1) and, breast cancer resistance protein, three members of the ATP-binding cassette transporter family was not modified over passages. Our results suggest a novel resistance mechanism, probably not involving the mechanisms usually observed in vitro.

MeSH terms

  • Abdominal Neoplasms / drug therapy
  • Abdominal Neoplasms / pathology
  • Animals
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Camptothecin / analogs & derivatives*
  • Camptothecin / therapeutic use*
  • Cell Division / drug effects
  • Child, Preschool
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Irinotecan
  • Male
  • Mice
  • Mice, Nude
  • Neuroblastoma / drug therapy
  • Neuroblastoma / pathology*
  • Topoisomerase I Inhibitors*
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents, Phytogenic
  • Topoisomerase I Inhibitors
  • Irinotecan
  • Camptothecin