Effects of PTK787/ZK222584, a tyrosine kinase inhibitor, on the growth of a poorly differentiated thyroid carcinoma: an animal study.
The process of neoangiogenesis is induced by several mediators. Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis including thyroid carcinomas. The principal aim of this study was to test the hypothesis that inhibition of VEGF activity by PTK787/ZK222584 (PTK/ZK), a specific blocker of both VEGF-receptor tyrosine kinases, could inhibit the growth of a poorly differentiated thyroid cancer. Human follicular thyroid tumor xenografts were implanted sc into nude mice. Eight days following implantation, the animals were randomized into two groups (n = 10 each group). One group received PTK/ZK daily, and the other was treated with sodium chloride (control). Treatment was orally administered using a gastric tube. All animals were killed after 4 wk. Tumors, blood, and samples of other organs were taken for further examinations. Treatment with PTK/ZK induced a 41.4% reduction in tumor volumes. Necrosis of the tumors was detectable earlier in PTK/ZK-treated mice compared with controls. Immunohistochemistry revealed a significant decrease in neoangiogenesis in tumors of PTK/ZK-treated animals. Moreover, no compensatory overexpression of VEGF protein was detectable in the treated group. The compound was well tolerated by the animals without significant side effects on body weight or in general. These results showed that VEGF receptor blockade is a rational approach to the therapy of thyroid cancer. The combination of radioiodine or external radiation with VEGF receptor tyrosine kinase inhibitors might be a new option, especially for poorly differentiated thyroid cancers with limited or no response to conventional therapy.
Schoenberger
Johann
J
Department of Nuclear Medicine, University of Regensburg, 93042 Regensburg, Germany. johann.schoenberger@klinik.uni-regensburg.de
Grimm
Daniela
D
Kossmehl
Peter
P
Infanger
Manfred
M
Kurth
Ekkehard
E
Eilles
Christoph
C
D018263:Adenocarcinoma, Follicular / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010793:Phthalazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines; D013954:Thyroglobulin / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D016326:Extracellular Matrix Proteins; D010793:Phthalazines; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; C404768:vatalanib; D013954:Thyroglobulin; D011505:Protein-Tyrosine Kinases