In vivo treatment with CPT-11 leads to differentiation of neuroblastoma xenografts and topoisomerase I alterations.
Topoisomerase I inhibitors, such as CPT-11, are potent anticancer drugs against neuroblastoma (NB). Differentiating agents, such as retinoids, improve the survival of children with metastatic NB. To characterize the biological effects associated with exposure to CPT-11 in vivo, athymic mice bearing a human NB xenograft, named IGR-NB8 and characterized as an immature NB with poor prognostic markers, were treated with CPT-11. Prolonged stable disease was observed, resulting in an overall tumor growth delay of 115 days. During treatment, tumors differentiated into ganglioneuroblastomas (GGNB), which reverted into an immature phenotype when treatment was discontinued. In contrast, 13-cis retinoic acid failed to induce differentiation of IGR-NB8 in vivo. Tumor differentiation was associated with decreased N-myc expression, induction of p73 expression in the perinuclear area and cytoplasm, and a dramatic 35-fold decrease in topoisomerase I (topo I) catalytic activity. The full-length Mr 100,000 topo I protein was present in both pre and post-treatment immature NB xenografts. In contrast, differentiated GGNBs did not contain the Mr 100,000 protein but an intense Mr 48,000 topo I fragment. Furthermore, redistribution of the Mr 48,000 and 68,000 forms to the cytoplasm was observed in differentiated tumors. The same pattern of topo I expression and catalytic activity was observed in NBs and GGNBs obtained from pediatric patients. Our data suggest that prolonged in vivo exposure to CPT-11 induces differentiation of NB xenografts, which is associated with truncation of the topo I enzyme, relocation of the degraded forms to the cytoplasm, and decreased catalytic activity.
Santos
Alexandre
A
Laboratory of Pharmacology and New Treatments of Cancers, Institut Gustave-Roussy, Villejuif, and Aventis Pharma, Vitry sur Seine, France.
Calvet
Loreley
L
Terrier-Lacombe
Marie-Josee
MJ
Larsen
Annette
A
Bénard
Jean
J
Pondarré
Corinne
C
Aubert
Geneviève
G
Morizet
Jackie
J
Lavelle
François
F
Vassal
Gilles
G
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004224:Diterpenes; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D012172:Retinaldehyde / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; C031338:13-cis-retinal; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D012172:Retinaldehyde; D002166:Camptothecin