PTK 787/ZK 222584, a Tyrosine Kinase Inhibitor of all Known VEGF Receptors, Represses Tumor Growth with High Efficacy

Abstract

The angiogenesis inhibitor PTK 787/ZK 222584 (PTK/ZK) blocks all known VEGF receptor (VEGFR) tyrosine kinases, including the lymphangiogenic VEGFR3, in the lower nanomolar range. From a panel of 100 kinases only PDGFR, c-kit, and c-fms are inhibited beyond those in the nanomolar range. PTK/ZK functions as a competitive inhibitor at the ATP-binding site of the receptor kinase as shown here in kinetic experiments. The VEGF signal blockade in microvascular endothelial cells (MVEC) results in a blockade of MVEC proliferation (IC50=30 nM), without affecting the proliferation of normal tissue cells and tumor cells. The efficacy of PTK/ZK depends on its continuous presence within the endothelial target cells. Early removal attenuates its antiproliferative activity in vitro. Growth inhibition of endothelial cells is fully reversible as demonstrated by "washout" experiments. Without inhibiting tumor cell proliferation directly, PTK/ZK results in a significant retardation of tumor growth in a number of experimental tumor models of different tissue origin. Combination of PTK/ZK with an antiandrogen revealed additive effects on tumor-growth inhibition. Treatment efficacy was monitored both by tumor weight and by the determination of serum concentrations of the surrogate marker PSA. PTK/ZK is currently being investigated in patients with different solid tumor types for its therapeutic utility. Preliminary data from phase I/II clinical trials of PTK/ZK as a monotherapy suggested a positive safety and tolerability profile, which we interpret to be a consequence of the high selectivity of the drug for a limited number of kinases. Preliminary response, time to progression, and overall survival data were promising.1 Based on these encouraging results, PTK/ZK is currently in Phase III clinical trials for metastatic colorectal cancer.

The expression of VEGF receptor genes is concurrently influenced by epigenetic gene silencing of the genes and VEGF activation

“…Finally, a 128 bp fragment of KDR were amplified using primers (KDR-CBR-F; 5' AGT TTT TAT TTT GTA TTG AGT TT 3', KDR-CBR-R; 5' AAA ATA TCC AAA CTA CCA AAC 3') ( The paracrine angiogenic VEGF pathway is more frequently targeted than the autocrine pathway in efforts to prevent cancer progression by an anticancer drug such as VEGF-specific tyrosine kinase inhibitor. [20][21][22] The autocrine VEGF-VEGFR signaling functions to maintain homeostasis 23 and mitogenesis within the cell. 5,8,10,15,24 So, the autocrine pathway in cancer cells could be a therapeutic target for a VEGF-specific tyrosine-kinase inhibitor.…”

Inhibition of Multiple Vascular Endothelial Growth Factor Receptors (VEGFR) Blocks Lymph Node Metastases but Inhibition of VEGFR-2 Is Sufficient to Sensitize Tumor Cells to Platinum-Based Chemotherapeutics

“…PTK787/ZK222584 (PTK/ ZK; vatalanib, Novartis Pharma/Schering AG; ref. 21), a potent pan-VEGFR TKI, inhibits angiogenesis, tumor growth, and metastasis formation in experimental carcinoma models (22,23). PTK/ZK has displayed activity in early clinical trials (24,25).…”

A Fuller Understanding of Pancreatic Neuroendocrine Tumours Combined with Aggressive Management Improves Outcome

“…Multitargeted tyrosine kinase receptor inhibitors, such as PTK/ZK, have a high affinity for all VEGFRs and platelet-derived growth factor receptors, inhibiting tumour neovascularisation [125] . Studies using experimental tumour models, animal models and early phases of clinical trials have reported promising anti-tumour effects of PTK/ZK [126][127][128][129] . Further clinical trials are necessary to confirm the efficacy of this agent in the treatment of PNETs.…”