The Curative Efficacy of Namitecan (ST1968) in Preclinical Models of Pediatric Sarcoma Is Associated With Antiangiogenic Effects

Biochem Pharmacol. 2012 Jul 15;84(2):163-71. doi: 10.1016/j.bcp.2012.04.005. Epub 2012 Apr 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacokinetics
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Bevacizumab
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology
  • Chemokine CCL2 / metabolism
  • Chemokine CXCL16
  • Chemokines, CXC / metabolism
  • DNA Topoisomerases, Type I / metabolism
  • Female
  • Fibroblast Growth Factor 2 / metabolism
  • Humans
  • Indoles / pharmacology
  • Mice
  • Mice, Nude
  • Pyrroles / pharmacology
  • Receptors, Scavenger / metabolism
  • Rhabdomyosarcoma / drug therapy
  • Rhabdomyosarcoma / metabolism
  • Rhabdomyosarcoma / pathology
  • Sarcoma / drug therapy*
  • Sarcoma / metabolism
  • Sarcoma / pathology
  • Sunitinib
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • CXCL16 protein, human
  • Chemokine CCL2
  • Chemokine CXCL16
  • Chemokines, CXC
  • Indoles
  • Pyrroles
  • Receptors, Scavenger
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Fibroblast Growth Factor 2
  • Bevacizumab
  • DNA Topoisomerases, Type I
  • Sunitinib
  • namitecan
  • Camptothecin