COMPARATIVE EFFICACY OF ANTI-VEGF AGENTS IN WILMS TUMOR

Huang J, Soffer S, Kim E, McCrudden K, Yamashiro D, and Kandel J.

College of Physicians and Surgeons, Columbia University, NY, USA

 

Objective: Vascular endothelial growth factor (VEGF) is implicated in angiogenesis in many human tumors, but the relative role of VEGF isoforms and other VEGF family members is unknown. VEGF is expressed in human Wilms tumor and in derived xenografts in mice.  We have studied 3 different anti-VEGF agents: an RNA-based aptamer directed at VEGF165, a humanized monoclonal antibody binding all human VEGF-A isoforms, and a novel construct of VEGF receptors -1 and -2 that binds multiple VEGF family members (VEGF Trap) of human and animal origin. We hypothesized that treatment with agents addressing different VEGF targets would suppress Wilms tumor xenografts with differing efficacy. 

Methods: 106 cultured human anaplastic Wilms tumor cells were implanted intrarenally in athymic mice.  In 3 experiments, animals received intraperitoneal injections of either aptamer (n=10), antibody (n=13), VEGF Trap (n=10) or vehicle (Control n=10,15,10 respectively), for 5 weeks prior to sacrifice. Vasculature was mapped by fluorescein angiography and PECAM-1 immunostaining. Apoptosis was assessed by TUNEL assay and VEGF expression by RT-PCR.  Control/treated tumor weights were compared by Kruskal-Wallis analysis.

Results: Aptamer resulted in 84% tumor suppression, VEGF antibody 95%, and VEGF -Trap 98% suppression (p<0.028, <0.0001, <0.0001 respectively). Angiography and PECAM-1 immunostaining demonstrated sparce vascularity in treated xenografts. TUNEL assay revealed endothelial apoptosis in treated but not control tumors. RT-PCR confirmed VEGF expression in all xenografts in similar quantities.

Conclusions: Anti-VEGF agents with different spectra of activity effectively inhibit growth and angiogenesis in a xenograft model of anaplastic Wilms tumor. Differences in efficacy may reflect the contributions of VEGF-A isoforms besides VEGF165 or other VEGF family members.  The use of such anti-VEGF strategies may represent an effective new option for the treatment of aggressive Wilms tumor.

 

 

 
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