PTK787/ZK 222584 enhances efficacy of cytostatics in human xenografts and does not interfere with their uptake in tumor tissue.

Proc Amer Assoc Cancer Res, Volume 45, 2004 2373 The inhibition of neo-angiogenesis is a new treatment paradigm in cancer therapy intended to stop the disease progress and to shift the disease from an acute to a chronic state. Favourable in vitro and animal experiments with PTK787/ZK222584 (PTK/ZK), an angiogenesis inhibitor blocking the known VEGF receptor kinases, were translated in phase I and I/II studies and revealed encouraging efficacy associated with a favourable side effect profile in patients after once daily oral treatment. Two double blind, controlled phase III studies in first and second line colon cancer therapy have started recently (CONFIRM 1 and CONFIRM 2). The efficacy and low side effect profile of the compound is explained by its high selectivity for VEGFR 1, 2 and 3, c-fms, c-kit, and PDGFR. VEGF receptors were inhibited in cellular assays with IC50s between 20-50 nM; c-fms, c-kit and PDGFR kinases are inhibited 10 fold weaker. Other kinases were not inhibited up to 100-fold concentrations. VEGF receptor kinase inhibition blocks endothelial cell proliferation and migration without affecting tumor cells directly. PDGFR inhibition destabilizes the interaction of endothelium with the pericytes and the smooth muscle cells. The anti angiogenic effects of PTK/ZK resulted in efficacious inhibition of tumor growth in various models, without impairing animal weights. Since combination therapy is predominant for the majority of cancer indications, we performed a number of experiments combining a cytostatic agent and PTK/ZK for therapy. In the hormone-dependent prostate tumor model CWR22 we used a combination with an anti androgen (CPA) and measured the prostate specific antigen (PSA) as a biomarker. The drug combination inhibited tumor growth similarly well as orchiectomy and led to a simultaneous decrease of the PSA levels. PTK/ZK combined with taxol in the lung tumor model A 549 neither influenced toxicity nor weight gain compared to taxol treatment alone, whereas the efficacy in tumor growth inhibition was additive. Similar results were obtained with models for mammary and colon carcinomas as well as melanoma (MATU, HT29 and B16F10). To analyze the role of permeability reduction (VEGF= V ascular P ermeability F actor) by PTK/ZK in more detail, we investigated the consequences of a pretreatment with PTK/ZK followed by an application of cytostatic agents: We found no change of the uptake of the cytostatics in tumors after pretreatment with PTK/ZK using two independent analytical methods.In conclusion, combinations of PTK/ZK with cytostatics and antihormones were superior to a single agent treatment. There was no change in tolerability. Thus, PTK/ZK is well tolerated and may represent an additional treatment option for solid tumors either as single agent or in combination therapy. * PTK787/ZK 222584 is being co-developed by Schering AG, Germany and Novartis, Switzerland