title: Adenovirus-mediated gene therapy with an antiangiogenic fragment of thrombospondin-1 inhibits human leukemia xenograft growth in nude mice.
abstract: 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.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, 288 Nanjing Road, Tianjin 300020, PR China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Yan-Han
authors.initials: YH
authors.lastname: Li
authors.forename: Chen
authors.initials: C
authors.lastname: Yang
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Zhou
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Shi-Hong
authors.initials: SH
authors.lastname: Lu
authors.forename: Ren-Chi
authors.initials: RC
authors.lastname: Yang
authors.forename: Ying-Lin
authors.initials: YL
authors.lastname: Cai
authors.forename: Gerard
authors.initials: G
authors.lastname: Tobelem
authors.forename: Jacques
authors.initials: J
authors.lastname: Caen
authors.forename: Zhong Chao
authors.initials: ZC
authors.lastname: Han
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000235:genetics / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D019700:Thrombospondin 1 / Q000008:administration & dosage* / Q000235:genetics / Q000494:pharmacology; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D019700:Thrombospondin 1