PTK787/ZK 222584, a specific vascular endothelial growth factor-receptor tyrosine kinase inhibitor, affects the anatomy of the tumor vascular bed and the functional vascular properties as detected by dynamic enhanced magnetic resonance imaging.
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.
Department of Medical Oncology, Tumor Biology Center, 79106 Freiburg, Germany. drevs@tumorbio.uni-freiburg.de
Joachim
J
Drevs
Ralph
R
Müller-Driver
Christine
C
Wittig
Stefan
S
Fuxius
Norbert
N
Esser
Harald
H
Hugenschmidt
Moritz A
MA
Konerding
Peter R
PR
Allegrini
Jeanette
J
Wood
Jürgen
J
Hennig
Clemens
C
Unger
Dieter
D
Marmé
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism; D001808:Blood Vessels / Q000033:anatomy & histology / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000098:blood supply* / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000097:blood; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000188:drug therapy; D018810:Magnetic Resonance Angiography; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009942:Organometallic Compounds / Q000097:blood; D010793:Phthalazines / Q000494:pharmacology*; D011725:Pyridines; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor; D012039:Regional Blood Flow / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D010793:Phthalazines; D011725:Pyridines; D017978:Receptors, Growth Factor; C404768:vatalanib; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; C017807:bisbenzimide ethoxide trihydrochloride