Fiche publication
Date publication
septembre 2004
Journal
British journal of cancer
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MERLIN Jean-Louis
Tous les auteurs :
Calvet L, Santos A, Valent A, Terrier-Lacombe MJ, Opolon P, Merlin JL, Aubert G, Morizet J, Schellens JH, Bénard J, Vassal G
Lien Pubmed
Résumé
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.
Mots clés
Abdominal Neoplasms, drug therapy, Animals, Antineoplastic Agents, Phytogenic, therapeutic use, Camptothecin, analogs & derivatives, Cell Division, drug effects, Child, Preschool, Drug Resistance, Neoplasm, Female, Humans, Male, Mice, Mice, Nude, Neuroblastoma, drug therapy, Topoisomerase I Inhibitors, Transplantation, Heterologous
Référence
Br. J. Cancer. 2004 Sep;91(6):1205-12
