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

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J Pediatr Surg. 2001 Aug;36(8):1177-81

Soffer SZ, Moore JT, Kim E, Huang J, Yokoi A, Manley C, O'Toole K, Stolar C, Middlesworth W, Yamashiro DJ, Kandel JJ.

Division
of Pediatric Surgery, and the Department of Pathology, College of
Physicians and Surgeons, Columbia University, New York, NY, USA.
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growth accelerates if antibody is withdrawn.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.