title: The curative efficacy of namitecan (ST1968) in preclinical models of pediatric sarcoma is associated with antiangiogenic effects.
abstract: Namitecan (ST1968), a novel hydrophilic camptothecin analog of the 7-oxyiminomethyl series, was selected for clinical development on the basis of its promising preclinical efficacy. Since there is clinical evidence of efficacy of camptothecins against pediatric tumors, this study was performed to explore the antitumor and antiangiogenic activity of the camptothecin derivative in pediatric sarcoma models. With the exception of an undifferentiated rhabdomyosarcoma (A204), namitecan exhibited curative efficacy even at well-tolerated suboptimal doses in a panel of five models. The good therapeutic index of namitecan likely reflected a high and persistent drug accumulation at tumor site. The four responsive tumors were characterized by high topoisomerase I expression. In the RD/TE-671 rhabdomyosarcoma model the drug activity was associated with a marked antiangiogenic effect, which was consistent with the downregulation of proangiogenic factors, including VEGF, bFGF and the multifunctional chemokines CCL-2 and CXCL16. In agreement with this modulation, the combination of low doses of namitecan with other antiangiogenic agents, such as bevacizumab (a humanized anti-VEGF antibody) and sunitinib (a multitarget tyrosine kinase inhibitor effective against receptors implicated in the angiogenesis process), enhanced the antitumor effects. In conclusion, this preclinical study provides evidence of curative efficacy of namitecan at well-tolerated doses against pediatric sarcoma models, likely reflecting a contribution of antiangiogenic effects. Based on the promising therapeutic profile, namitecan is a good candidate for clinical evaluation in pediatric sarcomas.
authors.affiliation: Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cassinelli
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuco
authors.forename: Giovanna
authors.initials: G
authors.lastname: Petrangolini
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.forename: Monica
authors.initials: M
authors.lastname: Tortoreto
authors.forename: Cinzia
authors.initials: C
authors.lastname: Lanzi
authors.forename: Denis
authors.initials: D
authors.lastname: Cominetti
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.forename: Augusto
authors.initials: A
authors.lastname: Orlandi
authors.forename: Daniela
authors.initials: D
authors.lastname: Passeri
authors.forename: Daniela
authors.initials: D
authors.lastname: Meco
authors.forename: Angela Maria
authors.initials: AM
authors.lastname: Di Francesco
authors.forename: Riccardo
authors.initials: R
authors.lastname: Riccardi
authors.forename: Federica
authors.initials: F
authors.lastname: Bucci
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000068258:Bevacizumab; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000378:metabolism; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D011758:Pyrroles / Q000494:pharmacology; D051116:Receptors, Scavenger / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077210:Sunitinib; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C423727:CXCL16 protein, human; D018932:Chemokine CCL2; D000075743:Chemokine CXCL16; D019743:Chemokines, CXC; D007211:Indoles; D011758:Pyrroles; D051116:Receptors, Scavenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D000068258:Bevacizumab; D004264:DNA Topoisomerases, Type I; D000077210:Sunitinib; C531200:namitecan; D002166:Camptothecin