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.