Adenovirus-mediated delivery of a soluble form of the VEGF receptor Flk1 delays the growth of murine and human pancreatic adenocarcinoma in mice.
BACKGROUND
Because pancreatic adenocarcinoma is poorly responsive to chemotherapy and radiation therapy, novel treatments such as antiangiogenic gene therapy may have use in the adjuvant treatment of this malignancy. We evaluated the antitumor effects of the in vivo administration of an adenovirus vector encoding a soluble form of Flk1 (Flk1-Fc), a receptor for vascular endothelial growth factor, in 3 murine models of pancreatic adenocarcinoma.


METHODS
In a first model, immunocompetent C57Bl/6 mice were injected subcutaneously with Panc02 murine pancreatic adenocarcinoma cells before treatment. In a second model, immunodeficient severe combined immunodeficiency mice were injected subcutaneously with BxPc-3 human pancreatic adenocarcinoma cells before treatment. In a third model, C57Bl/6 mice were injected with Panc02 cells through an intrasplenic route before treatment, in an effort to model metastatic disease. In each model, half the tumor-bearing mice were injected intravenously with 10(9) Flk1-Fc adenovirus particles and half with control adenovirus.


RESULTS
In subcutaneous tumor models, Ad Flk1-Fc-treated animals were found to have 75% smaller murine and 78% smaller human pancreatic tumor volumes, relative to tumor volumes of Ad Fc-treated animals, 6 weeks after vector administration. In animals injected with tumor through the intrasplenic route, pathologic and histologic analyses made 10 days after injection of tumor revealed hepatic, pancreatic, and splenic tumors, together with a desmoplastic response consistent with pathologic findings in human pancreatic cancer. Cohorts of these tumor-bearing mice treated with Ad Flk1-Fc demonstrated significantly longer survival and decreased liver replacement with tumor at the time of death, relative to animals treated with Ad Fc.


CONCLUSIONS
A recombinant adenovirus encoding soluble Flk-1 inhibited pancreatic tumor growth in mice. These studies suggest that the delivery of gene products such as Flk1-Fc through in vivo gene transfer may be useful in the future treatment of patients with pancreatic cancer.
Tseng
Jennifer F
JF
Department of Genetics, Harvard Medical School, and Division of Molecular Medicine, Children's Hospital, and Surgical Research Laboratories, Children's Hospital, Boston, Mass 02115, USA.
Farnebo
Filip A
FA
Kisker
Oliver
O
Becker
Christian M
CM
Kuo
Calvin J
CJ
Folkman
Judah
J
Mulligan
Richard C
RC
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology* / Q000556:secondary; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D012995:Solubility; D013160:Splenic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D014407:Tumor Cells, Cultured; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000627:therapeutic use*
D040301:Vascular Endothelial Growth Factor Receptor-2