Adenovirus-mediated gene therapy with an antiangiogenic fragment of thrombospondin-1 inhibits human leukemia xenograft growth in nude mice.
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.
Liu
Peng
P
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.
Wang
Yi
Y
Li
Yan-Han
YH
Yang
Chen
C
Zhou
Yu-Ling
YL
Li
Bin
B
Lu
Shi-Hong
SH
Yang
Ren-Chi
RC
Cai
Ying-Lin
YL
Tobelem
Gerard
G
Caen
Jacques
J
Han
Zhong Chao
ZC
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
D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D019700:Thrombospondin 1