Adenovirus-mediated gene therapy with an antiangiogenic fragment of thrombospondin-1 inhibits human leukemia xenograft growth in nude mice

• Published in: Leukemia research 2003-08, Vol.27 (8), p.701-708
• Main Authors: Liu, Peng, Wang, Yi, Li, Yan-Han, Yang, Chen, Zhou, Yu-Ling, Li, Bin, Lu, Shi-Hong, Yang, Ren-Chi, Cai, Ying-Lin, Tobelem, Gerard, Caen, Jacques, Han, Zhong Chao
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Adenovirus; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Angiogenesis; Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - genetics; Angiogenesis Inhibitors - pharmacology; Animals; Applied cell therapy and gene therapy; Biological and medical sciences; Cell Division - drug effects; Female; Gene therapy; Genetic Therapy - methods; Genetic Vectors; Hematologic and hematopoietic diseases; Humans; K562 cell line; K562 Cells; Leukemia; Leukemia - therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Nude; Neovascularization, Pathologic - drug therapy; Peptide Fragments - administration & dosage; Peptide Fragments - genetics; Peptide Fragments - pharmacology; Thrombospondin 1 - administration & dosage; Thrombospondin 1 - genetics; Thrombospondin 1 - pharmacology; Thrombospondin-1; Transduction, Genetic; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation, Heterologous; Treatment Outcome
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/S0145-2126(02)00346-6

Recent investigations support the idea that angiogenesis is involved in the pathophysiology of leukemia. Within a given microenvironment, the angiogenic response is regulated by a delicate balance of angiogenesis inducers and inhibitors. Thrombospondin-1 (TSP-1) is a multifunctional extracellular glycoprotein showing angiostatic properties in multiple in vitro and in vivo assays. Interestingly, there is also proangiogenic domain in this complex molecule. Development of TSP-1 as an antiangiogenic drug has been hindered by multiplicity of its functional effects, difficulties in its production and its poor pharmacokinetics. The aim of the present study was to establish a recombinant adenovirus (ADV·TSP-1 f) expressing antiangiogenic fragment of TSP-1 (TSP-1 f), and to determine the feasibility for use of the adenovirally expressed TSP-1 f in leukemia gene therapy. The results of this investigation showed that TSP-1 f was expressed efficiently in adenovirus-transduced human myelogenous leukemia K562 cells. Compared to the controls, although there was almost no effect on proliferation of K562 cells in vitro, adenovirus-mediated TSP-1 f transduction inhibited the growth of K562 xenografts dramatically. Furthermore, the microvessel density (MVD) was much lower in the ADV·TSP-1 f-treated tumors compared to the controls. These data support the use of in vivo gene delivery approach to produce antiangiogenic fragment of TSP-1 for leukemia therapy.