Specific targeting of tumor vasculature by diphtheria toxin-vascular endothelial growth factor fusion protein reduces angiogenesis and growth of pancreatic cancer.
J Gastrointest Surg
; 6(2): 159-66; discussion 166, 2002.
Article
em En
| MEDLINE
| ID: mdl-11992800
ABSTRACT
Tumor vessels abundantly express receptors for vascular endothelial growth factor (VEGF), a mediator of neoangiogenesis. The aim of this study was to specifically target and damage the vasculature of pancreatic cancer (PaCa) by fusing VEGF to diphtheria toxin (DT), which inhibits protein synthesis of target cells. DT-VEGF fusion protein was produced in vector pGEX-KG and expressed in E. coli SG12036. Human PaCa cell lines (HPAF-2 and AsPC-1) and human endothelial cells (HUVEC) were exposed to DT-VEGF (10 ng/ml - 10,000 ng/ml). Proliferation was assessed after 3 days. One mm(3) fragments of subcutaneous PaCa donor tumors were implanted into the pancreas of nude mice that received either DT-VEGF (200 microg/kg, every other day) or phosphate-buffered saline intraperitoneally for 14 weeks. Tumor volume, metastatic spread, and animal weight were determined at autopsy. Microvessel density was analyzed in CD31-stained tumor sections. Proliferation of PaCa cells was inhibited at high concentrations of DT-VEGF (>1000 ng/ml). DT-VEGF decreased the growth of HUVEC at 10 ng/ml. In vivo, DT-VEGF reduced tumor volume (HPAF-2, 76%; AsPC-1, 53%), microvessel density (HPAF-2, 54%; AsPC-1, 62%), and tumor spread (HPAF-2, 89%; AsPC-1, 50%). Survival was increased (HPAF-2, 7/8 vs. 4/8 animals; AsPC-1, 6/8 vs. 1/8 animals). Weight was not influenced by DT-VEGF. The DT-VEGF effect is due to its toxic action on the tumor vasculature rather than to direct inhibition of PaCa cell growth. DT-VEGF therapy was not associated with systemic side effects.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
/
Fatores de Crescimento Endotelial
/
Linfocinas
/
Inibidores da Angiogênese
/
Toxina Diftérica
/
Neovascularização Patológica
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2002
Tipo de documento:
Article