No topoisomerase I alteration in a neuroblastoma model with in vivo acquired resistance to irinotecan.
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.
Pharmacology and New Treatments in Cancer (UPRES EA 3535), Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France.
L
L
Calvet
A
A
Santos
A
A
Valent
M-J
MJ
Terrier-Lacombe
P
P
Opolon
J-L
JL
Merlin
G
G
Aubert
J
J
Morizet
J H M
JH
Schellens
J
J
Bénard
G
G
Vassal
D000008:Abdominal Neoplasms / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology*; D059004:Topoisomerase I Inhibitors; D014183:Transplantation, Heterologous
D000972:Antineoplastic Agents, Phytogenic; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin