1. ¹State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
2. ²National Engineering Research Center of Cell Products, AmCellGene Co. Ltd, TEDA, Tianjin, People's Republic of China

Correspondence: Dr ZC Han, Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union of Medical College, 288 Nanjing Road, Tianjin 300020, China. E-mail: tihzchan@public.tpt.tj.cn

Received 28 July 2005; Revised 19 September 2005; Accepted 20 September 2005; Published online 10 November 2005.

Abstract

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.