title: Vascular endothelial growth factor receptor tyrosine kinase inhibitors: PTK787/ZK 222584.
abstract: PTK787/ZK 222584 (PTK/ZK) is an oral potent and selective inhibitor of the vascular endothelial growth factor (VEGF)-mediated Flt-1 and KDR receptor tyrosine kinases. PTK/ZK has been shown to reduce growth and microvasculature in subcutaneously implanted human tumor xenografts in nude mice. A clinical difficulty in evaluating angiogenesis inhibitors has been the usefulness of conventional study endpoints. Therefore, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been studied as a pharmacodynamic marker of efficacy of PTK/ZK. Phase I studies are under way evaluating the optimum dose and schedule of oral PTK/ZK administered continuously to patients with advanced cancers of types known to overexpress VEGF. To date, particularly in patients with liver metastases from colorectal cancer treated with PTK/ZK, DCE-MRI has been a useful predictor of the biological response of VEGF-receptor inhibition. Toxicities have been manageable and have included lightheadedness, ataxia, nausea, vomiting, and hypertension. Stabilization of disease for >/= 6 months has been seen in heavily pretreated patients receiving PTK/ZK at higher doses. Preliminary data suggest that PTK/ZK can be administered safely on a continuous daily dosing schedule, efficacy data look promising, and DCE-MRI correlates with biological response. DCE-MRI will be used to guide dose optimization of PTK/ZK and perhaps of other angiogenesis inhibitors in future studies.
authors.affiliation: Leicester Royal Infirmary, Leicester, UK.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Thomas
authors.forename: Bruno
authors.initials: B
authors.lastname: Morgan
authors.forename: Joachim
authors.initials: J
authors.lastname: Drevs
authors.forename: Clemens
authors.initials: C
authors.lastname: Unger
authors.forename: Bertram
authors.initials: B
authors.lastname: Wiedenmann
authors.forename: Udo
authors.initials: U
authors.lastname: Vanhoefer
authors.forename: Dirk
authors.initials: D
authors.lastname: Laurent
authors.forename: Margaret
authors.initials: M
authors.lastname: Dugan
authors.forename: William P
authors.initials: WP
authors.lastname: Steward
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003287:Contrast Media; D004354:Drug Screening Assays, Antitumor; D005682:Gadolinium; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D008279:Magnetic Resonance Imaging; D010793:Phthalazines / Q000494:pharmacology*; D011725:Pyridines; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D003287:Contrast Media; D010793:Phthalazines; D011725:Pyridines; C404768:vatalanib; D005682:Gadolinium; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2