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Departments of Surgery (B. R., J. J. C.), Radiation Oncology (C. W., J. L., L. W. O, J. J. C.), and the Holden Comprehensive Cancer Center (J. M. R., L. W. O., J. J. C.), University of Iowa College of Medicine, Iowa City, Iowa 52242, and Veterans Affairs Medical Center (M. M. H., J. J. C.), Iowa City, Iowa 52242

² To whom requests for reprints should be addressed, at 4605 JCP, University of Iowa Hospitals and Clinics, Iowa City, IA 52242. Phone: (319) 353-8297; Fax: (319) 356-8378; E-mail: joseph-cullen{at}uiowa.edu

Cells contain a large number of antioxidants to prevent or repair the damage caused by reactive oxygen species. One component of the antioxidant system, manganese superoxide dismutase (MnSOD), is localized in the mitochondria, and the levels of this protein have been previously shown to inversely correlate with pancreatic cancer cell growth. The aim of the present study was to determine whether MnSOD overexpression could suppress the in vitro and in vivo malignant phenotype of a human pancreatic cancer cell line. Tumor cell behavior was determined in the pancreatic cancer cell line MIA PaCa-2 by examining cell growth, plating efficiency, and anchorage-independent growth in soft agar. MnSOD was overexpressed in the pancreatic cancer cell line MIA PaCa-2 by infection with an adenovirus-MnSOD construct. Cells were also injected s.c. in nude mice and tumor volume was calculated. Single and multiple direct injections of the adenoviral MnSOD construct (10⁹ plaque-forming units) were delivered to the tumor. Increases in MnSOD immunoreactivity and activity were seen after transduction with the adenovirus-MnSOD construct. Increasing MnSOD levels correlated with increased doubling time. Cell growth, plating efficiency, and growth in soft agar decreased with increasing amounts of the adenovirus MnSOD construct. Tumors grew slower and survival was increased in nude mice injected with the adenoviral MnSOD construct compared with the parental cell line, whereas multiple injections of the adenoviral MnSOD construct further inhibited tumor cell growth and extended survival. These results suggest that MnSOD may be a tumor suppressor gene in human pancreatic cancer. Delivery of the MnSOD gene may prove beneficial for suppression of pancreatic cancer growth.

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