Abstract A262: Antiangiogenic proprieties of E-3810, a new dual inhibitor of VEGF and FGF receptors

• Published in: Molecular cancer therapeutics 2009-12, Vol.8 (12_Supplement), p.A262-A262
• Main Authors: Giavazzi, Raffaella, Oliva, Paolo, Taraboletti, Giulia, Berndt, Alexander, Colombo, Sonia, Valbusa, Giovanni, Cavalletti, Ennio, Cereda, Roberta, Damia, Giovanna, Camboni, Gabriella
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-09-A262

E-3810, 6-[[7-[(1-aminocyclopropyl)methoxy]-6-methoxy-4-quinolyl]oxy]-N-methyl-naphthalene-1-carboxamide, is a novel small molecule that potently and selectively inhibits VEGFR1-3 and FGFR-1 tyrosine kinases. E-3810 has shown antitumor activity against various types of cancer xenografts with good tolerability. The anti-angiogenic proprieties of E-3810 were investigated in vitro on endothelial cells and in vivo in angiogenesis-induced models and human tumor xenografts. E-3810 inhibited VEGF- and FGF-2-induced HUVEC (human umbilical vein endothelial cells) proliferation with an IC50 of 40–50 nM. The ability of E-3810 to inhibit angiogenesis in vivo was assessed in the Matrigel plug assay, where angiogenesis is induced by FGF-2 embedded in Matrigel pellets, implanted subcutaneously in mice. Treatment with E-3810 (20 mg/kg p.o., daily for 6 days) completely inhibited the angiogenic response measured by hemoglobin content. The effect on tumor angiogenesis was investigated in the human A498 renal carcinoma xenografted subcutaneously in nude mice. Oral treatment with E-3810 for up 30 days at the optimal antitumor dose of 20 mg/kg led to significant tumor growth delay (Treated -Controls = 24 days). E-3810 significantly decreased blood vessel density and increased vessel maturation index (assessed by immunostaining with anti CD31 and CD31/ SMA antibodies); this was accompanied by decreased expression of stroma collagen IV and increased tumor necrosis. A498 xenografts growing in nude mice were also analyzed by DCE-MRI (dynamic contrast-enhanced magnetic resonance imaging) before and after 5 and 12 days of oral treatments with 20 mg/kg E- 3810. The kinetic analysis of the distribution of the contrast agent (Gadocoletic Acid Trisodium Salt, B22956/1, Bracco S.p.a., Italy) showed significant reduction in perfusion, calculated applying the IAUC method over the first 30 minutes post contrast injection, in E-3810 treated tumors compared with both baseline values and untreated controls already after 5 days of treatment. These results show a significant antiangiogenic activity of E-3810, which is likely to contribute to its potent antitumor activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A262.