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Intact Nitric Oxide Synthase II Gene Is Required for Interferon-ß-mediated Suppression of Growth and Metastasis of Pancreatic Adenocarcinoma¹

Departments of Gastrointestinal Medical Oncology [B. W., Q. X., Q. S., X. L., J. L. A., K. X.], and Cancer Biology [K. X.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Previous studies have shown that enforced expression of IFN-ß suppressed tumor growth and metastasis. In this report, we determined whether the induction of nitric oxide synthase II (NOS II) gene is required for IFN-ß-mediated antitumor activity using syngeneic mice with intact (NOS II^+/+) or genetically disrupted (NOS II^-/-) NOS II gene. PANC02-H7 highly metastatic murine pancreatic adenocarcinoma cells were transfected with an IFN-ß expression vector or a control pcDNA3 vector. The parental PANC02-H7, control vector-transfected, and IFN-ß-transfected cells were orthotopically implanted into the pancreas of syngeneic NOS II^+/+ and NOS II^-/- C57BL/6J mice. In NOS II^+/+ C57BL/6J, both parental and control vector-transfected cells grew progressively in pancreas and produced numerous liver metastases and a large amount of malignant ascites, whereas IFN-ß-secreting cells did not. In NOS II^-/- C57BL/6J mice, however, IFN-ß-secreting cells grew much more aggressively. Higher NO induction was detected in NOS II^+/+ mice that received injections with IFN-ß-secreting cells than with the control cells, but it was not detected in NOS II^-/- mice. These data suggested that IFN-ß secreted from tumor cells stimulates NO production by host cells and suppresses tumor growth and metastasis.

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