title: Resistance of a VEGF-producing tumor to anti-VEGF antibody: unimpeded growth of human rhabdoid tumor xenografts.
abstract: OBJECTIVE
  Rhabdoid tumor of the kidney (RTK) is a lethal malignancy of childhood for which there currently are no effective therapies. Because vascular endothelial growth factor (VEGF) is nearly ubiquitous in human tumors, the authors hypothesized that a xenograft model of RTK would (1) express VEGF and (2) respond to anti-VEGF intervention.
  
  
  METHODS
  A total of 2 x 10(6) cultured RTK cells were implanted intrarenally (G-401) in athymic mice. Control/treated animals received either vehicle (phosphate-buffered saline, PBS) or anti-VEGF antibody (anti-VEGF) for 5 weeks (n = 20, 17, respectively). Vasculature was mapped by angiography and immunostaining. Apoptosis was assessed by TdT-mediated dUTP nick end labeling (TUNEL) assay, VEGF expression examined by reverse transcription polymerase chain reaction, and tumor weights compared by Kruskal-Wallis analysis.
  
  
  RESULTS
  Mean tumor weights were not altered significantly by anti-VEGF (0.78-g, controls v 0.56-g treated tumors; P value, not significant). Grossly, xenografts grew in a novel manner, encasing rather than invading the kidney, and did not metastasize. PECAM-1 immunostaining and fluorescein angiography showed similar vascularity in control and treated xenografts. Both apoptosis and VEGF expression were unchanged in treated specimens.
  
  
  CONCLUSIONS
  Unexpectedly, growth of RTK xenografts was not inhibited by specific anti-VEGF antibody, although these tumors express significant amounts of VEGF. In addition, RTK vasculature, apoptosis, and VEGF expression were not substantially altered by anti-VEGF antibody. These results suggest that tumor-derived VEGF is of highly variable importance in different malignancies.
authors.affiliation: Division of Pediatric Surgery, Department of Pathology, College of Physicians and Surgeons, Columbia University, NY, USA.
authors.forename: Samuel Z
authors.initials: SZ
authors.lastname: Soffer
authors.forename: Eugene
authors.initials: E
authors.lastname: Kim
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Huang
authors.forename: Kimberly
authors.initials: K
authors.lastname: McCrudden
authors.forename: Akiko
authors.initials: A
authors.lastname: Yokoi
authors.forename: James T
authors.initials: JT
authors.lastname: Moore
authors.forename: Christina
authors.initials: C
authors.lastname: Manley
authors.forename: Kathleen
authors.initials: K
authors.lastname: O'Toole
authors.forename: William
authors.initials: W
authors.lastname: Middlesworth
authors.forename: Charles
authors.initials: C
authors.lastname: Stolar
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Yamashiro
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Kandel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000276:immunology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008222:Lymphokines / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D016612:Paraffin Embedding; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology; D018335:Rhabdoid Tumor / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D014183:Transplantation, Heterologous / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors