The Type 1 Repeat Peptide Abt510 Induces Apoptosis Of Brain Microvascular Endothelial Cells And Inhibits Glioblastoma Tumor Growth In Vivo

229 The targeting of angiogenesis in malignant tumors is an important new therapeutic approach. Type 1 repeat peptides from thrombospondin-1 have been shown to inhibit angiogenesis in vitro. Angiogenesis is a prominent characteristic of glioblastoma tumor biopsies; therefore, we investigated the ability of a modified type 1 repeat peptide (NAcSarGlyValDalloIleThrNvaIleArgProNHE, ABT510) to induce apoptosis of brain microvessel endothelial cells (MvEC) propagated in vitro and to inhibit tumor growth in an intracerebral xenograft model of glioblastoma. We found that ABT510 treatment of brain MvEC induced apoptosis, evidenced by caspase-3 cleavage, in a dose- and time-dependent manner that was also caspase-8 dependent. ABT510 inhibited in a similar dose- and caspase-8-dependent manner tube formation and branching of brain MvEC propagated on collagen gels. In an intracerebral xenograft model of glioblastoma (U-251MG cells), tumors that were established for 7 days, followed by treatment with ABT510 peptide (339 mg/kg mouse weight/day, days 7-19), euthanasia, harvesting of the brains, and a histologic analysis, resulted in a 57% reduction in tumor volume as compared to animals treated with saline (p= 0.015). Also, microvessel density was reduced by 40% in the ABT510-treated animals as compared to saline-treated animals (42.5 microvessels per mm2 area of tumor versus 25 microvessels per mm2 area of tumor; p=0.017). These data suggest that the ABT510 peptide inhibits glioblastoma tumor growth by inhibiting angiogenesis and is a potential new therapeutic option for patients with this highly malignant tumor.