Antiangiogenic
therapy based on blocking the actions of
vascular endothelial growth factor-A (
VEGF) can lead to "normalization" of blood vessels in both animal and human
tumors. Differential expression of
VEGF isoforms affects
tumor vascular maturity, which could influence the normalization process and response to subsequent treatment.
Fibrosarcoma cells expressing only VEGF120 or VEGF188
isoforms were implanted either subcutaneously (s.c.) or in dorsal skin-fold "window" chambers in SCID mice. VEGF120 was associated with vascular fragility and
hemorrhage.
Tumor-bearing mice were treated with repeat doses of
SU5416, an
indolinone receptor tyrosine kinase inhibitor with activity against
VEGFR-2 and proven preclinical ability to induce
tumor vascular normalization.
SU5416 reduced vascularization in s.c. implants of both VEGF120 and VEGF188
tumors. However, in the window chamber,
SU5416 treatment increased red cell velocity in VEGF120 (representing vascular normalization) but not VEGF188
tumors.
SU5416 treatment had no effect on growth or
necrosis levels in either
tumor type but tended to counteract the increase in interstitial fluid pressure seen with growth of VEGF120
tumors.
SU5416 pretreatment resulted in the normally fragile blood vessels in VEGF120-expressing
tumors becoming resistant to the vascular damaging effects of the
tubulin-binding vascular disrupting agent (VDA),
combretastatin A4 3-O-phosphate (CA4P). Thus, vascular normalization induced by antiangiogenic treatment can reduce the efficacy of subsequent VDA treatment. Expression of VEGF120 made
tumors particularly susceptible to vascular normalization by
SU5416, which in turn made them resistant to CA4P. Therefore,
VEGF isoform expression may be useful for predicting response to both antiangiogenic and vascular-disrupting
therapy.