Treatment of metastatic colorectal carcinomas by systemic inhibition of vascular endothelial growth factor signaling in mice.
OBJECTIVE
Tumor angiogenesis has been shown to be promoted by vascular endothelial growth factor (VEGF) via stimulating endothelial cell proliferation, migration, and survival. Blockade of VEGF signaling by different means has been demonstrated to result in reduced tumor growth and suppression of tumor angiogenesis in distinct tumor entities. Here, we tested a recombinant adenovirus, AdsFlt1-3, that encodes an antagonistically acting fragment of the VEGF receptor 1 (Flt-1), for systemic antitumor effects in pre-established subcutaneous CRC tumors in mice.


METHODS
Murine colorectal carcinoma cells (CT26) were inoculated subcutaneously into Balb/c mice for in vivo studies. Tumor size and survival were determined. 293 cell line was used for propagation of the adenoviral vectors. Human lung cancer line A549 and human umbilical vein endothelial cells were transfected for in vitro experiments.


RESULTS
Infection of tumor cells with AdsFlt1-3 resulted in protein secretion into cell supernatant, demonstrating correct vector function. As expected, the secreted sFlt1-3 protein had no direct effect on CT26 tumor cell proliferation in vitro, but endothelial cell function was inhibited by about 46% as compared to the AdLacZ control in a tube formation assay. When AdsFlt1-3 (5 x 10(9) PFU/animal) was applied to tumor bearing mice, we found a tumor inhibition by 72% at d 12 after treatment initiation. In spite of these antitumoral effects, the survival time was not improved. According to reduced intratumoral microvessel density in AdsFlt1-3-treated mice, the antitumor mechanism can be attributed to angiostatic vector effects. We did not detect increased systemic VEGF levels after AdsFlt1-3 treatment and liver toxicity was low as judged by serum alanine aminotransferase determination.


CONCLUSIONS
In this study we confirmed the value of a systemic administration of AdsFlt1-3 to block VEGF signaling as antitumor therapy in an experimental metastatic colorectal carcinoma model in mice.
Schmitz
Volker
V
Medizinische Klinik I, Sigmund-Freud-Str. 25, Bonn 53105, Germany. volker.schmitz@ukb.uni-bonn.de
Kornek
Miroslaw
M
Hilbert
Tobias
T
Dzienisowicz
Christian
C
Raskopf
Esther
E
Rabe
Christian
C
Sauerbruch
Tilman
T
Qian
Cheng
C
Caselmann
Wolfgang-H
WH
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002461:Cell Line, Transformed; D015179:Colorectal Neoplasms / Q000556:secondary* / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D007668:Kidney / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*
D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1