Inhibition of human leukemia xenograft in nude mice by adenovirus-mediated tissue inhibitor of metalloproteinase-3.

Considerable studies have demonstrated the pivotal roles of matrix metalloproteinases (MMPs) in leukemia dissemination and extramedullary infiltration. Tissue inhibitors of matrix metalloproteinases (TIMPs) are multifunctional proteins with MMPs inhibitory effects. However, little is known about the application of TIMPs in the treatment of leukemia. Here, we investigated the effects of TIMP-3 overexpression via adenoviral gene delivery on the in vitro growth and invasiveness of leukemic cells and the in vivo progress of K562-derived xenografts in nude mice. The in vitro invasiveness of K562 cells was markedly impaired by AdTIMP-3 infection. Moreover, TIMP-3 significantly inhibited K562-derived angiogenic factors-induced proliferation, migration and bFGF-induced tube formation of endothelial cells (ECs) in vitro, and reduced VEGF-induced gelatinases expression and activation in ECs. Although TIMP-3 overexpression had no direct effect on the growth of K562 cells in vitro, repeated intratumoral injection of AdTIMP-3 significantly inhibited the growth of K562 xenografts in nude mice. Furthermore, lower microvessel density, less vessel maturity and increased apoptosis were observed in AdTIMP-3-treated K562 xenografts, suggesting the importance of antiangiogenic action of TIMP-3. These data demonstrated the potential of applying AdTIMP-3 as an effective antiangiogenic adjuvant in the treatment of leukemia progression.