A combination of plasmid DNAs encoding murine fetal liver kinase 1 extracellular domain, murine interleukin-12, and murine interferon-gamma inducible protein-10 leads to tumor regression and survival in melanoma-bearing mice.
The vascular endothelial growth factor (VEGF) and its interaction with the vascular endothelial growth factor receptor 2 [VEGFR2/murine fetal liver kinase 1 (Flk-1), human kinase domain receptor] are an important angiogenic pathway leading to tumor vascularization. A plasmid DNA encoding the complete extracellular domain (ECD) of murine Flk-1 including the endogenous signal sequence was designed as a possible competitor of the receptor to sequester VEGF. The plasmid DNA was used to treat B16F10 cell-induced subcutaneous melanomas in syngeneic mice. The Flk-1 ECD-encoding plasmid DNA injected intramuscularly did not lead to tumor reduction. However, intratumoral injection caused a dose-dependent reduction and significant retardation of tumor growth. Blood vessels analyzed by immunohistochemistry with anti-CD31 antibodies as indicators of vascularization appeared smaller in diameter after treatment. A combination of Flk-1 ECD and DNA encoding murine interleukin-12 or murine interferon-gamma inducible protein-10 improved the effect, leading to tumor regression and long-term survival of the mice.
Ladell
Kristin
K
Institute of Medical Virology, University of Zurich, Gloriastrasse 30, 8028, Zurich, Switzerland.
Heinrich
Jochen
J
Schweneker
Marc
M
Moelling
Karin
K
D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics*; D004247:DNA / Q000737:chemistry*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D018664:Interleukin-12 / Q000235:genetics*; D008545:Melanoma / Q000401:mortality* / Q000628:therapy*; D008546:Melanoma, Experimental / Q000401:mortality / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D017434:Protein Structure, Tertiary; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis* / Q000235:genetics*
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018664:Interleukin-12; D004247:DNA; D040301:Vascular Endothelial Growth Factor Receptor-2