Systemic Treatment with the Antiangiogenic Agent ABT-510 Inhibited Myeloma-Induced Microvessels and Tumor Growth in Myelomatous SCID-hu Mice.

Abstract

Myeloma cells induce bone marrow angiogenesis and increased microvessel density (MVD) is associated with poor prognosis in this disease. The aim of this study was to investigate whether neovascularization is required for myeloma growth by testing the anti-angiogenesis and anti-tumor efficacy of thrombospondin-1 (TSP-1)-derived mimetic peptide, ABT-510 (Abbott Laboratories), in the SCID-hu model for primary myeloma. TSP-1 is a matricellular glycoprotein with multiple biological functions, including antiangiogenic activity. ABT-510 is a capped nonapeptide based on the linear TSP-1 heptapeptide sequence. Like TSP-1, ABT-510 can be targeted to a specific receptor on vascular endothelial cells and efficiently inhibits angiogenesis in vitro and after systemic injection in experimental models of human malignancies. SCID-hu mice were constructed as previously described (Yaccoby et al., Blood 1998; 1999; 2002). Myelomatous SCID-hu mice were prepared by injection of myeloma cells from 6 patients into the implanted human bone in the hosts. Changes in levels of tumor burden were monitored by weekly measurements of human monotypic immunoglobulins (hIg) using ELISA and histologically confirmed by immunohistochemical staining of human bone sections for cIg. MVD, visualized by CD34 staining, were counted in 4 non-overlapping areas. Upon establishment of myeloma growth (401±146 μg/ml pre-treatment levels) mice were intraperitoneally injected with ABT-510 (100 mg/kg, twice a day) or with the vehicle (5% dextrose) for 4–10 weeks. Treatment was well tolerated and no sign of toxicity or reductions in body weight were observed. Whereas all dextrose -treated mice had increased hIg levels during the experimental period, ABT-510 treatment resulted in marked reduction of tumor burden in 2 experiments by 48% and 20%, respectively, retardation of myeloma growth in 3 additional experiments and no response in one experiment. Overall, tumor burden in control- and ABT-510-treated mice was increased by 3696%±3264 and 448%±169 from pre-treatment levels, respectively (p<0.03). MVD in control- and ABT-510-treated mice were 21±6/mm2 and 11±4/mm2, respectively (p<0.02). Intriguingly, MVD in the non-responding mouse was reduced by >35% (11±2 vs. 17±1 microvessels/MM2 in control mouse, p<0.04), suggesting that certain myeloma cells are not dependent on neovascularization. We conclude that myeloma cells from the majority of patients require angiogenesis for growth and that ABT-510, which is undergoing a phase II clinical trial for treating solid tumors, is a potential agent for treating myeloma.