title: Distinct response of experimental neuroblastoma to combination antiangiogenic strategies.
abstract: BACKGROUND
  The authors have shown previously that experimental neuroblastoma is partially inhibited (48%) by antivascular endothelial growth factor (anti-VEGF) antibody. The topoisomerase-I inhibitor, topotecan, has been shown to have antiangiogenic activity when administered in a low-dose, high-frequency regimen. We hypothesized that combining topotecan with anti-VEGF would suppress neuroblastoma more effectively than either agent alone.
  
  
  METHODS
  A total of 10(6) neuroblastoma cells were implanted intrarenally in athymic mice. Animals received vehicle, topotecan, anti-VEGF, or topotecan plus anti-VEGF (n = 9, 20, 20, 20, respectively). All control and half the treated mice were killed at 6 weeks. Remaining (rebound) mice were maintained without treatment for 3 more weeks. Patterns of vasculature and apoptosis were determined immunohistochemically.
  
  
  RESULTS
  Tumor weights at 6 weeks were reduced significantly in topotecan-only (0.07g) and combination-treated animals (0.08 g), compared with controls or anti-VEGF--treated mice (1.18 g, 0.53 g; P <.0007, all). At 9 weeks, rebound tumor weights were greatest in anti-VEGF (2.82 g), intermediate in topotecan (1.82 g), and least in combination-treated animals (1.47 g); however, the only significant difference was between anti-VEGF and combination therapy (P = 0.04). All treated tumors were vascularized sparsely in comparison with controls at 6 weeks, but exhibited brisk neoangiogenesis at 9 weeks.
  
  
  CONCLUSIONS
  Topotecan either with or without anti-VEGF antibody significantly suppresses neuroblastoma xenograft growth in comparison with controls or anti-VEGF antibody alone. Combining topotecan with anti-VEGF antibody significantly inhibited rebound tumor growth in comparison with anti-VEGF antibody alone. Combination therapy may improve durability of antiangiogenic inhibition of neuroblastoma.
authors.affiliation: Division of Pediatric Surgery, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Eugene S
authors.initials: ES
authors.lastname: Kim
authors.forename: Samuel Z
authors.initials: SZ
authors.lastname: Soffer
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Huang
authors.forename: Kimberly W
authors.initials: KW
authors.lastname: McCrudden
authors.forename: Akiko
authors.initials: A
authors.lastname: Yokoi
authors.forename: Christina A
authors.initials: CA
authors.lastname: Manley
authors.forename: William
authors.initials: W
authors.lastname: Middlesworth
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Kandel
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Yamashiro
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000276:immunology; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D008222:Lymphokines / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy*; D009447:Neuroblastoma / Q000098:blood supply* / Q000188:drug therapy*; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D008222:Lymphokines; D059004:Topoisomerase I Inhibitors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019772:Topotecan