Porphyrin analogues as novel antagonists of fibroblast growth factor and vascular endothelial growth factor receptor binding that inhibit endothelialcell proliferation, tumor progression, and metastasis

Fibroblast growth factors (FGFs) and vascular endothelial growth factor (VE GF) play a pivotal role in the multistep pathway of tumor progression, meta stasis, and angiogenesis, We have identified a porphyrin analogue, 5,10,15, 20-tetrakis(methyl-4-pyridyl)-21H,23H-porphine-tetra-p-tosylate salt (TMPP) , as a potent inhibitor of FGF2 and VEGF receptor binding and activation. T MPP demonstrated potent inhibition of binding of soluble FGF receptor 1 (FG FR1) to FGF2 immobilized on heparin at submicromolar concentrations. TMPP i nhibits binding of radiolabeled FGF2 to FGFR in a cell-free system as well as to cells genetically engineered to express FGFR1, Furthermore, TMPP also inhibits the binding of VEGF to its tyrosine kinase receptor in a dose-dep endent manner. In an in vitro angiogenic assay measuring the extent of endo thelial cell growth, tube formation, and sprouting, TMPP dramatically reduc ed the extent of the FGF2-induced endothelial cell outgrowth and differenti ation. In a Lewis Lung carcinoma model, mice receiving TMPP showed a marked inhibition of both primary tumor progression and lung metastases developme nt, with nearly total inhibition of the metastatic phenotype upon alternate daily injections of TMPP at 25 mu g/g of body mass. Finally, novel meso-py ridylium-substituted, nonsymmetric porphyrins, as well as a novel corrole-b ased derivative, with >50-fold increase in activity in vitro, had a signifi cantly improved efficacy in blocking tumor progression and metastasis in vi vo.