Combination antiangiogenic therapy: increased efficacy in a murine model of Wilms tumor

J Pediatr Surg. 2001 Aug;36(8):1177-81. doi: 10.1053/jpsu.2001.25747.


Background/purpose: Antibody to vascular endothelial growth factor (anti-VEGF) suppresses tumor growth and metastasis in experimental Wilms tumor. However, tumor growth accelerates if antibody is withdrawn. As recently shown, low-dose, frequently administered topotecan, a topoisomerase-1 inhibitor, has anti-angiogenic activity. The authors hypothesized that combined topotecan/anti-VEGF therapy would suppress tumor growth and metastasis more durably than either agent alone.

Methods: Xenografts were induced by intrarenal injection of human Wilms tumor cells in athymic mice (n = 59). Mice were divided into control (n = 10), anti-VEGF (n = 16), topotecan (n = 17), and topotecan plus anti-VEGF (n = 16) groups. All control and half the treated mice were killed at week 6. Remaining ("rebound") mice were maintained without treatment until week 8. Tumor vasculature was mapped by fluorescein angiography/PECAM immunostaining. Endothelial apoptosis was assessed by TUNEL assay.

Results: 6 weeks: Tumor weights were reduced significantly in treated mice (P <.003 v control). Seven of ten control and 1 of 25 treated mice displayed lung metastases (P <.003). Rebound tumors were largest in topotecan-only, intermediate in antibody-treated, and smallest in combination-treated mice. Immunostaining and angiography results showed sparse vascularity in treated xenografts. Endothelial apoptosis was observed only in treated tumors.

Conclusion: Combination low-dose topotecan and anti-VEGF antibody therapy is antiangiogenic and suppresses tumor growth and metastasis in experimental Wilms tumor more durably than either agent alone.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biopsy, Needle
  • Disease Models, Animal
  • Endothelial Growth Factors / administration & dosage
  • Endothelial Growth Factors / immunology
  • In Situ Nick-End Labeling
  • Injections, Intraperitoneal
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / pathology
  • Lymphokines / administration & dosage
  • Lymphokines / immunology
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / prevention & control*
  • Reference Values
  • Sensitivity and Specificity
  • Survival Rate
  • Topotecan / administration & dosage
  • Treatment Outcome
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Wilms Tumor / drug therapy*
  • Wilms Tumor / pathology


  • Antibodies, Monoclonal
  • Endothelial Growth Factors
  • Lymphokines
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Topotecan