Inhibition of vascular endothelial growth factor (VEGF) as a novel approach for cancer therapy.

:Of the numerous growth factors and cytokines that have been shown to have angiogenic effects, vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), appears to be a key factor in pathological situations which involve neovascularization as well as enhanced vascular permeability. Our aim was to design a low molecular weight synthetic molecule that potently and selectively blocks the VEGF/VEGF receptor system after oral administration, suitable for the chronic therapy of VEGF-dependent pathological neovascularization. PTK787/ZK 222584 is a potent inhibitor of VEGF receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, like the PDGFR-beta tyrosine kinase, c-Kit and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families such as EGFR, FGFR-1, c-Met and Tie-2 or intracellular kinases like c-Src, c-Abl, PKC-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of KDR, and endothelial cell proliferation, migration and survival in the nanomolar range in cell based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or anti-proliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF- and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown subcutaneously in nude mice, as well as a murine renal carcinoma and its metastases in syngeneic, orthotopic models. Histological examination of tumors reveals inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 also significantly inhibits ascites formation induced by a human ovarian carcinoma grown in the peritoneum of nude mice as well as pleural effusion induced by a human lung adenocarcinoma in nude mice. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent, or impair hematopoetic recovery following concomitant cytotoxic anti-cancer agent challenge. These studies indicate that compounds that inhibit the effects of VEGF, such as PTK787/ZK 222584, have the potential to provide a novel, effective and well-tolerated therapy for the treatment of solid tumors. These agents may also provide a new therapeutic approach for the treatment of other diseases where angiogenesis plays an important role.

Wood JM 《MEDICINA-BUENOS AIRES》

PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration.

Wood JM ，Bold G ，Buchdunger E ，Cozens R ，Ferrari S ，Frei J ，Hofmann F ，Mestan J ，Mett H ，O'Reilly T ，Persohn E ，Rösel J ，Schnell C ，Stover D ，Theuer A ，Towbin H ，Wenger F ，Woods-Cook K ，Menrad A ，Siemeister G ，Schirner M ，Thierauch KH ，Schneider MR ，Drevs J ，Martiny-Baron G ，Totzke F ... -  《CANCER RESEARCH》

Treatment for malignant pleural effusion of human lung adenocarcinoma by inhibition of vascular endothelial growth factor receptor tyrosine kinase phosphorylation.

Yano S ，Herbst RS ，Shinohara H ，Knighton B ，Bucana CD ，Killion JJ ，Wood J ，Fidler IJ ... -  《CLINICAL CANCER RESEARCH》

CEP-7055: a novel, orally active pan inhibitor of vascular endothelial growth factor receptor tyrosine kinases with potent antiangiogenic activity and antitumor efficacy in preclinical models.

Ruggeri B ，Singh J ，Gingrich D ，Angeles T ，Albom M ，Yang S ，Chang H ，Robinson C ，Hunter K ，Dobrzanski P ，Jones-Bolin S ，Pritchard S ，Aimone L ，Klein-Szanto A ，Herbert JM ，Bono F ，Schaeffer P ，Casellas P ，Bourie B ，Pili R ，Isaacs J ，Ator M ，Hudkins R ，Vaught J ，Mallamo J ，Dionne C ... -  《CANCER RESEARCH》

Effect of VEGF receptor inhibitor PTK787/ZK222584 [correction of ZK222548] combined with ionizing radiation on endothelial cells and tumour growth.

Hess C ，Vuong V ，Hegyi I ，Riesterer O ，Wood J ，Fabbro D ，Glanzmann C ，Bodis S ，Pruschy M ... -  《-》