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Expression of Manganese Superoxide Dismutase Reduces Tumor Control Radiation Dose: Gene-Radiotherapy¹

Department of Radiation Medicine [M. U., M. K., R. R.] and the Graduate Center for Toxicology [D. K. S.], University of Kentucky Medical Center, Lexington, Kentucky 40536-0084, and Department of Pathology, University of Wisconsin, Madison, Wisconsin 53705 [T. D. O.]

This study investigated the in vitro and in vivo radiation response of tumor cells transfected with human manganese superoxide dismutase (MnSOD) cDNA. A major objective was to test the potential tumor suppressive effect of MnSOD in vivo. Tumor cells studied were an in vitro line derived from a murine spontaneous fibrosarcoma, FSa-II, which expressed an undetectable MnSOD activity. These cells were transfected with pSV2-NEO plasmid (NEO line) or cotransfected with MnSOD plasmid plus pSV2-NEO plasmid (SOD lines) as described previously. The cell lines used were SOD-L and SOD-H, which expressed, respectively, low and high MnSOD activities after transfection, and NEO and parental FSa-II controls. Both SOD-L and SOD-H cell lines were slightly more resistant to ionizing radiation than were the two control cell lines when irradiated in vitro in the presence of oxygen. The dose-modifying factors calculated at the survival level of 0.01 were 1.13 and 1.15 for the SOD-L and SOD-H cells, respectively. To investigate potential tumor suppressive effects, animal tumors of 4 mm diameter were irradiated in vivo under hypoxic conditions, and the radiation dose to control one-half of the irradiated tumors (TCD₅₀) was determined for each tumor. The TCD_50^S obtained on the basis of the tumor control rate in 120 days after irradiation were substantially lower for the SOD-H and SOD-L tumors compared to the N tumors. They were 22.9, 28.6, and 47.5 Gy for SOD-H, SOD-L and NEO tumors, respectively. To analyze these data, survival curves were obtained for hypoxic cells by irradiating NEO and SOD-H tumors under hypoxic conditions in vivo and assaying in vitro. Analysis of these curves suggests that the decrease in the TCD_50^S of SOD tumors is attributable to the reduced tumorigenicity in these tumors. The hypoxic cell survival curves also showed that SOD did not protect cells from radiation in the absence of oxygen. Electron microscopy showed no morphological differences between these cells. These results suggest that the fraction of tumorigenic cells could be reduced by expression of MnSOD, resulting in a substantial decrease in the TCD₅₀.

¹ This study was supported in part by American Cancer Society Grant EDT82-A, NIH Grant CA49797, Kentucky Tobacco Research Board Grant 5-41113, and a gene therapy grant from the University of Kentucky L. P. Markey Cancer Center (supported by the Ephraim McDowell Cancer Foundation).

² Present address: Department of Radiology, Okayama University, Okayama, Japan.

³ To whom requests for reprints should be addressed, at Graduate Center for Toxicology, University of Kentucky, 204 Funkhouser Building, Lexington, KY 40506-0054.

Received 3/24/95. Accepted 5/ 5/95.

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