To determine the level of
vascular endothelial growth factor (
VEGF)
protein produced in
tumor tissues and to evaluate the effect of
antisense oligonucleotides directed against
VEGF on
tumor growth and animal survival in a rabbit model of
leptomeningeal carcinomatosis. New Zealand White (NZW) rabbits were injected with VX2
tumor cells transfected with or without
VEGF antisense constructs. The time course of
VEGF protein expression in
tumor tissues was then examined by immunohistochemistry and western blot analysis.
VEGF concentrations in serum and cerebrospinal fluid (CSF) were determined by
enzyme-linked
immunosorbent assay (ELISA). The efficacy of
VEGF antisense
therapy was evaluated by calculation of the survival rate and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Immunohistochemical analysis and immunoblotting showed that
VEGF protein expression was significantly decreased in tissues from rabbits given
VEGF antisense treatment. Serum and CSF
VEGF concentrations were also markedly reduced during the first 15 days after
tumor inoculation in antisense-treated animals.
VEGF antisense
therapy resulted in prolonged animal survival. Furthermore, while some meningeal nodular enhancement was evident in almost all of the VX2-inoculated rabbits, meningeal enhancement and thickening was clearly suppressed after
VEGF antisense treatment. These results indicate that
VEGF antisense oligonucleotides have a potent anti-
tumor activity in a rabbit model of VX2
leptomeningeal carcinomatosis. In addition, DCE-MRI provides highly accurate measurements for the detection of experimentally induced
leptomeningeal carcinomatosis and could be used as a suitable method for assessing in vivo
tumor growth and angiogenesis.