Antiangiogenic
therapy is a promising new strategy of inhibiting
tumor growthand formation of
metastases. Recently, a number of compounds with different effects on
tumor endothelial cells have entered clinical trials and revealed the need for diagnostic methods to detect their biological activity. Dynamic enhanced magnetic resonance imaging (dyMRI) is used in most clinical trials with antiangiogenic active compounds. We evaluated this method by using
PTK787/
ZK 222584, a specific inhibitor of the
VEGF-receptor tyrosine kinases, which showed antitumoral and antiangiogenic activity in a murine
renal cell carcinoma (RENCA) model. After intrarenal application of RENCA cells, mice developed a primary
tumor and
metastases to the lung and abdominal lymph nodes. After daily oral
therapy for 21 days with either
PTK787/
ZK 222584 at a dose of 50 mg/kg or vehicle, primary
tumors of all animals were analyzed by dyMRI.
Gadolinium-DOTA (
Dotarem) was used as a
contrast agent to detect vessel permeability and
contrast agent extravasation, whereas intravascular iron oxide nanoparticles (
Endorem) were used to detect partial
tumor blood volume. Additionally, vessel density, architecture, diameter, and blood flow velocity were investigated by appropriate methods. Surprisingly, no changes in extravasation occurred under treatment with
PTK787/
ZK 222584 as compared with the control group, whereas a significant decrease in vessel permeability occurred. Furthermore, an increase in partial blood volume was found in the
PTK787/ZK 222584-treated group, although vessel density was reduced as seen by histology. Using the corrosion cast technique, reduction in vessel density was significant but not very pronounced and predominantly attributable to the loss of microvessels only. This finding correlated with a shift to large vessel diameters in the primary
tumors of
PTK787/ZK 222584-treated animals and with reduction of blood flow velocity in the
tumor feeding renal artery. From these findings, we conclude that the treatment with
PTK787/
ZK 222584 primarily reduces the number of
tumor microvessels, accompanied by a hemodynamic dilation of the remaining vessels. This dilation could influence the result of dyMRI such that no change in extravasation or even an increase in partial
tumor blood volume could be observed.