Angiogenesis, the formation of new vessels from an existing vascular network, is an essential event in a variety of physiological and pathological processes. Under physiological conditions, angiogenesis is restricted to processes such as embryogenesis, ovulation and wound healing. Angiogenesis also occurs in pathological processes such as inflammation, rheumatoid arthritis, ocular neovascularization, psoriasis and tumour growth and the formation of metastases. 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 that involve neovascularization as well as enhanced vascular permeability. Our aim was to design low molecular weight synthetic molecules that potently and selectively block the VEGF/VEGF receptor system after oral administration, suitable for the chronic therapy of VEGF-dependent pathological neovascularization.

One compound we developed is PTK787/ZK222584, a potent inhibitor of VEGF receptor tyrosine kinases active in the submicromolar range. It also inhibits other class III kinases, like the PDGFR-β 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 and PKC-α. PTK787/ZK222584 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 µM, it does not have any cytotoxic or anti-proliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg kg^-1) to mice, plasma concentrations of compound remain above 1 µM for more than 8 h. In doses of 25-100 mg kg^-1 P.O., PTK787/ZK222584 inhibits VEGF- and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumour cell-driven angiogenesis model. It also inhibits the growth of several human carcinomas, grown subcutaneously in nude mice, as well as the growth of metastases in syngeneic, orthotopic models. Various approaches used to visualise the vessels in the tumours have shown that PTK787/ZK222584 effectively reduces microvessels in the tumour, but does not affect larger vessels. Effects on tumour vessel permeability have been shown using an extravascular contrast agent and magnetic resonance imaging of tumours and metastases. Consistent with its ability to block vessel permeability, PTK787/ZK222584 has also been shown to significantly inhibit 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. This compound 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 leucocytes as a single agent, or impair haematopoetic recovery following concomitant cytotoxic chemotherapy.

These studies indicate that compounds that inhibit the effects of VEGF, such as PTK787/ZK222584, have the potential to provide a novel, effective and well-tolerated therapy for the treatment of a range of different solid tumours. These agents may also provide a new therapeutic approach for the treatment of other diseases where angiogenesis plays an important role.

Bold, G., Altmann, K.H., Frei, J. et al. (2000). J. Med. Chem. 43, 2310-2323.

Drevs, J., Hofmann, I., Hugenschmidt, H. et al. (2000). Cancer Res. 60, 4819-4824.

Kwak, N., Okamoto, N., Wood, J.M. & Campochiaro, P.A. (2000). Invest Ophthamol. Vis. Sci. 41, 3158-3164.

Ozaki, H., Seo, M.S., Ozaki, K. et al. (2000). Am. J. Pathol. 156, 697-707.

Wood, J.M., Bold, G., Buchdunger, E. et al. (2000). Cancer Res. 60, 2178-2189.

Xu, L., Yoneda, J., Herrera, C., Wood, J., Killion, J.J. & Fidler, I.J. (2000). Int. J. Oncol. 16, 445-454.

Yano, S., Herbst, R.S., Shinohara, H. et al. (2000). Clin. Cancer Res. 6, 957-965.