Anti-Angiogenesis

Tumours are very dependent on an extensive blood supply (vascularisation), to enable them to proliferate and metastasise. The degree of vascularisation has been linked to prognosis for a number of tumours, with more vascular tumours being more invasive and carrying a worse prognosis.

Vascular Endothelial Growth Factor (VEGF) is a cytokine which binds to specific receptors located on the inside lining of blood vessels (the endothelium), stimulating endothelial cell proliferation and thus promoting the formation of the new blood vessels (angiogenesis), which are required for the growth of both normal tissues and cancerous tissues.

VEGF also increases the permeability of blood vessels, making them more "leaky".

VEGF and/or the receptors for it are detectable in almost all types of tumours, and their blood vessels. Several studies in preclinical models, and more recently in clinical trials, have shown the efficacy of anti-VEGF cancer treatments in preventing VEGF-mediated angiogenesis and vascular permeability, resulting in control of the growth and spread of many tumour types, as well as reducing complications arising from fluid accumulation.

We have data to show that the inhibitory activity of PMX 464 and PMX 290 on HIF-1 signal transduction results in dose dependent inhibition of VEGF production, under both hypoxic and normoxic conditions. PMX 464 has also been shown to inhibit the proliferation and differentiation of human endothelial cells.

	Cytotoxic and antiangiogenic activity of AW464 (NSC 706704), a novel thioredoxin inhibitor: an in vitro study.

	Elucidation of thioredoxin as a molecular target for antitumour quinols.

	Induction and apoptosis without redox catastrophe by thioredoxin-inhibitory compounds.

	Novel thioredoxin inhibitors paradoxically increase Hypoxia-inducible factor-Î± expression but decrease functional transcriptional activity, DNA binding, and degradation.