Abstract
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 109 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. Conclusion. 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. (Surgery 2002;132:857-65.)
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Article info
Publication history
Accepted:
June 24,
2002
Footnotes
*Supported in part by a grant from AMGEN (R.C.M.). J.F.T. was supported by NIH grant 1 F32 CA 86420, an American College of Surgeons Resident Research Fellowship, and a Linton Fellowship from the Massachusetts General Hospital Department of Surgery. R.C.M is an equity-holding consultant with AMGEN.
**Reprint requests: Richard C. Mulligan, PhD, Children's Hospital, Enders 861, 320 Longwood Ave, Boston, MA 02115.
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Copyright
© 2002 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
