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

Background/Purpose: Antibody to vascular endothelial growth factor (anti-VE GF) suppresses tumor growth and metastasis in experimental Wilms tumor. How ever, tumor growth accelerates if antibody is withdrawn.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 topote can/anti-VEGF therapy would suppress tumor growth and metastasis more durab ly than either agent alone. Methods: Xenografts were induced by intrarenal injection of human Wilms tum or 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. Re maining ("rebound") mice were maintained without treatment until week 8. Tu mor 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 displaye d 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 treat ed xenografts. Endothelial apoptosis was observed only in treated tumors. Conclusion: Combination low-dose topotecan and anti-VEGF antibody therapy i s antiangiogenic and suppresses tumor growth and metastasis in experimental Wilms tumor more durably than either agent alone. J Pediatr Surg 38:1177-1 181. Copyright (C) 2001 by W.B. Saunders Company.