Details

Autor(en) / Beteiligte

• WOOD, J. M
• BOLD, G
• PERSOHN, E
• RÖSEL, J
• SCHNELL, C
• STOVER, D
• THEUER, A
• TOWBIN, H
• WENGER, F
• WOODS-COOK, K
• MENRAD, A
• SIEMEISTER, G
• BUCHDUNGER, E
• SCHIRNER, M
• THIERAUCH, K.-H
• SCHNEIDER, M. R
• DREVS, J
• MARTINY-BARON, G
• TOTZKE, F
• MARME, D
• COZENS, R
• FERRARI, S
• FREI, J
• HOFMANN, F
• MESTAN, J
• METT, H
• O'REILLY, T

Titel

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

Ist Teil von

• Cancer research (Chicago, Ill.), 2000-04, Vol.60 (8), p.2178-2189

Ort / Verlag

Philadelphia, PA: American Association for Cancer Research

Erscheinungsjahr

2000

Quelle

MEDLINE

Beschreibungen/Notizen

• PTK787/ZK 222584 (1-[4-chloroanilino]-4-[4-pyridylmethyl] phthalazine succinate) is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, such as the platelet-derived growth factor (PDGF) receptor beta tyrosine kinase, c-Kit, and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families, such as epidermal growth factor receptor, fibroblast growth factor receptor-1, c-Met, and Tie-2, or intracellular kinases such as c-Src, c-Abl, and protein kinase C-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of kinase insert domain-containing receptor (KDR), 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 antiproliferative 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 s.c. in nude mice, as well as a murine renal carcinoma and its metastases in a syngeneic, orthotopic model. Histological examination of tumors revealed inhibition of microvessel formation in the interior of the tumor. 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 after concomitant cytotoxic anti-cancer agent challenge. This novel compound has therapeutic potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.