title: Vascular endothelial growth factor monoclonal antibody inhibits growth of anaplastic thyroid cancer xenografts in nude mice.
abstract: BACKGROUND
  Anaplastic thyroid cancer (ATC) does not respond well to any treatment and is one of the most aggressive of all human cancers. Based on the importance of angiogenesis in solid tumor growth, we hypothesized that angiogenic blockade might reduce the growth of ATC.
  
  
  METHODS
  We tested the in vivo effect of vascular endothelial growth factor monoclonal antibody (VEGF-mAb) and thalidomide against ATC (ARO-81) xenografts in nude mice. Mice were injected subcutaneously with 1 x 10(6) ARO-81 cells, allowed to implant (1 week), and then given daily intraperitoneal injections of vehicle (control; n = 9), VEGF-mAb (200 microg/d; n = 9), or thalidomide (200 mg/kg per day; n = 9). Tumors were removed, sectioned, and stained for routine histology and immunohistochemistry.
  
  
  RESULTS
  At 6 weeks, VEGF-mAb-treated tumors were smaller (1603 +/- 296 mm(3)) than either the thalidomide-treated (6007 +/- 1498 mm(3); p = 0.008) or the control groups (4040 +/- 831 mm(3); p = 0.014) and the VEGF-mAb-treated animals maintained greater weight (30.4 +/- 0.84 g at week 6 versus thalidomide-treated, 26.0 +/- 0.94 g, p = 0.003; and control, 25.8 +/- 0.78 g, p = 0.001 animals). Central necrosis was observed in 3 of 9 VEGF-mAb-treated confidence interval (33%; 95% [CI] = 0.12-0.65) but in none of the control or thalidomide-treated tumors (0/18 total; 95% CI = 0.0-0.30; p = 0.029). VEGF staining intensity for VEGF-mAb- (2.0 +/- 0.24; p = 0.012) and thalidomide- (2.1 +/- 0.05; p = 0.052) treated tumors was greater than control (0.89 +/- 0.31) as was p53 staining grade (VEGF-mAb [1.3 +/- 0.37; p = 0.012]; thalidomide [1.0 +/- 0.41; p = 0.05]; and controls [0.11 +/- 0.11]).
  
  
  CONCLUSIONS
  We conclude that systemic VEGF-mAb significantly reduces growth of ATC xenografts and is associated with increased VEGF and p53 expression. Thalidomide has no effect on tumor growth, but is also associated with increased VEGF and p53 expression. These observations provide the first evidence that VEGF-mAb-induced angiogenesis blockade may be of use for the treatment of ATC.
authors.affiliation: Department of Pediatrics, Walter Reed Army Medical Center, Washington, DC, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bauer
authors.forename: Richard
authors.initials: R
authors.lastname: Terrell
authors.forename: Nalinikrishna K
authors.initials: NK
authors.lastname: Doniparthi
authors.forename: Aneeta
authors.initials: A
authors.lastname: Patel
authors.forename: R Michael
authors.initials: RM
authors.lastname: Tuttle
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Saji
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ringel
authors.forename: Gary L
authors.initials: GL
authors.lastname: Francis
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001835:Body Weight; D002277:Carcinoma / Q000473:pathology / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology*; D008222:Lymphokines / Q000032:analysis / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009336:Necrosis; D013792:Thalidomide / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000473:pathology / Q000628:therapy*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D013792:Thalidomide