Gene therapy of prostate cancer with the soluble vascular endothelial growth factor receptor Flk1.
A variety of novel therapeutic approaches have emerged recently for the treatment of human cancers. We have coupled two of these therapeutic approaches, gene therapy and antiangiogenic therapy and tested them in two murine prostate cancer models Recombinant adenovirus encoding the ligand-binding ectodomain of the VEGF receptor 2 (Flk1) fused to an Fc domain was administered to SCID mice carrying orthotopic human LNCaP tumors as well as to transgenic (TRAMP) mice with spontaneous prostate tumors. Ad Flk1-Fc injection reduced tumor growth by 66% for orthotopic LNCaP tumors and by 42% for spontaneous tumors in TRAMP mice. Microvessel density in the primary tumors was reduced by 68% and 40% in the two models respectively. A decrease in microvessel density was also observed in lymphatic metastases in Ad Flk1-Fc-treated TRAMP mice and was correlated with a decrease in the frequency of regional metastases in the treated animals. Survival time was also extended in the Ad Flk1-Fc-treated TRAMP mice relative to the control-treated animals. Our results suggest that adenoviral delivery of soluble Flk1 receptor can reduce vascular density and prostate tumor growth and prolong survival time in orthotopically implanted tumors as well as in spontaneous prostate tumors in transgenic animals.
Becker
Christian M
CM
Departments of Surgery and Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Farnebo
Filip A
FA
Iordanescu
Irina
I
Behonick
Danielle J
DJ
Shih
Mei-Chiung
MC
Dunning
Patricia
P
Christofferson
Rolf
R
Mulligan
Richard C
RC
Taylor
George A
GA
Kuo
Calvin J
CJ
Zetter
Bruce R
BR
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002460:Cell Line; D017690:Cell Transplantation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007700:Kinetics; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D011961:Receptors, Fc / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014183:Transplantation, Heterologous; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2; D017430:Prostate-Specific Antigen