Introduction: Pancreatic adenocarcinoma has a poor prognosis; conventional therapies offer minimal benefit. Since angiogenesis is required for solid tumor growth, antiangiogenic gene therapy may be a means to combat this malignancy. We investigated the effects of an adenovirus encoding an angiogenesis factor receptor on pancreatic adenocarcinoma growth in mice.
Methods: A recombinant adenovirus was constructed encoding Flk-1, a receptor for vascular endothelial growth factor (VEGF). Sixteen immunocompetent C57Bl/6 mice were injected subcutaneously with 5¥105 syngeneic murine pancreatic adenocarcinoma Panc02 cells. Sixteen immunodeficient SCID C57Bl/6 mice were injected with 106 BxPc-3 human pancreatic adenocarcinoma cells. In both groups, when tumors had reached 100-150 mm3 in volume, half the mice were injected with 109 Flk-1 adenovirus particles and half with control virus. Plasma Flk-1 levels were measured by ELISA. Tumor volumes were measured twice weekly.
Results: Flk-1 was detected at concentrations of 2-8 mg/ml by day 3 in treated mice. 3 weeks after injection of adenovirus, tumor curves diverged between the Flk-1 and control arms in both the murine (figure) and human pancreatic groups. After 6 weeks, Ad-Flk-1 treatment had resulted in 75% smaller murine and 85% smaller human pancreatic adenocarcinomas (p<0.001).
Conclusion: A recombinant adenovirus encoding the VEGF receptor Flk-1 slowed tumor growth in mice bearing both human and murine pancreatic adenocarcinomas. Antiangiogenic gene therapy may be useful in the future treatment of patients with pancreatic cancer.
