The anti-oxidant enzyme system protects cellular macromolecules against damage from reactive oxygen species. One component of this system, manganese superoxide dismutase (MnSOD), has also been shown to display tumor suppressor gene-like activity. The purpose of this study was to examine changes in MnSOD expression during hamster cheek pouch carcinogenesis, and the effects of MnSOD overexpression using an adenoviral vector. Tumor induction was carried out using 7,12-dimethylbenz[α]anthracene. Animals were killed at periodic intervals, and check pouch tissues were excised and examined for MnSOD expression by immunohistochemistry and digital image analysis. We observed a reduction in MnSOD expression as early as 2 weeks after the start of carcinogen application. Low MnSOD expression persisted until the end of the 23-week experimental period. Solid hamster cheek pouch carcinoma xenografts were then established in nude mice. An adenoviral vector encoding the human MnSOD gene was delivered to the xenografts by direct injection. We observed high, immediate expression of MnSOD in the xenografts that persisted for 10 days following cessation of viral construct delivery. Delivery of the MnSOD construct resulted in a maximal 50% reduction in tumor growth compared with untreated controls. Our results suggest that MnSOD may be a tumor suppressor gene in the hamster cheek pouch model system.
Akli S., Caillaud C., Vigne E., Stratford-Perricaudet LD, Poenaru L., Perricaudet M., et al. (1993). Transfer of a foreign gene into the brain using adenovirus vectors. Nat Genet3:224-228.
2.
Allen RG, Balin AK, Reimer RJ, Sohal RS, Nations C. (1988). Superoxide dismutase induces differentiation in microplasmodia of the slime mold, Physarum polycephalum. Arch Biochem Biophys261:205-211.
3.
Bannister JV, Bannister WH, Rotilio G. (1987). Aspects of the structure, function, and applications of superoxide dismutase. CRC Crit Rev Biochem22:111-180.
4.
Beckman BS, Balin AK, Allen RG (1989). Superoxide dismutase induces differentiation of Friend erythroleukemia cells. J Cell Physiol139:370-376.
5.
Blanco CE, Sieck GC, Edgerton VR (1988). Quantitative histochemical determination of succinic dehydrogenase activity in skeletal muscle fibres. Histochem J20:240-243.
6.
Bravard A., Sabatier L., Hoffschir F., Ricoul M., Luccioni C., Dutrillaux B. (1992). SOD2: a new type of tumor-suppressor gene? Int J Cancer51:476-480.
7.
Chang LY, Slot JW, Geuze HJ, Crapo JD (1988). Molecular immunocytochemistry of the CuZn superoxide dismutase in rat hepatocytes. J Cell Biol107:2169-2179.
8.
Chen SH, Shine HD, Goodman JC, Grossman RG, Woo SL (1994). Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. Proc Natl Acad Sci USA91:3054-3057.
9.
Christensen TG (1984). The distribution and function of peroxidases in the respiratory tract. Surv Synth Pathol Res3:201-218.
10.
Church SL, Grant JW, Ridnour LA, Oberley LW, Swanson PE, Meltzer PS, et al. (1993). Increased manganese superoxide dismutase expression suppresses the malignant phenotype of human melanoma cells. Proc Natl Acad Sci USA90:3113-3117.
11.
Clayman GL, Trapnell BC, Mittereder N., Liu TJ, Eicher S., Zhang S., et al. (1995). Transduction of normal and malignant oral epithelium by an adenovirus vector: the effect of dose and treatment time on transduction efficiency and tissue penetration. Cancer Gene Ther2:105-111.
12.
Cui XL, Douglas JG (1997). Arachidonic acid activates c-jun N-terminal kinase through NADPH oxidase in rabbit proximal tubular epithelial cells. Proc Natl Acad Sci USA94:3771-3776.
13.
Cutright DE, Bauer H. (1967). Cell renewal in the oral mucosa and skin of the rat. I. Turnover time. Oral Surg Oral Med Oral Pathol23:249-259.
14.
Darby CJ, Smith B., Lam EW, Oberley LW (1998). BCNU cytotoxicity is enhanced by overexpression of antioxidant enzymes in vitro and in vivo (abstract). Free Radic Biol Med25 (Suppl 1):S116.
15.
Davidson BL, Allen ED, Kozarsky KF, Wilson JM, Roessler BJ (1993). A model system for in vivo gene transfer into the central nervous system using an adenoviral vector. Nat Genet3:219-223.
16.
Diaz-Araya CM, Provis JM, Billson FA (1993). NADPH-diaphorase histochemistry reveals cone distributions in adult human retinae. Aust NZJOphthalmol21:171-179.
17.
Eastham JA, Hall SJ, Sehgal I., Wang J., Timme TL, Yang G., et al. (1995). In vivo gene therapy with p53 or p21 adenovirus for prostate cancer. Cancer Res55:5151-5155.
18.
Fernandez-Pol JA, Hamilton PD, Klos DJ ( 1982). Correlation between the loss of the transformed phenotype and an increase in superoxide dismutase activity in a revertant subclone of sarcoma virus-infected mammalian cells. Cancer Res42:609-617.
19.
Fischer C., Bond CP ( 1972). The quantimet 720D for densitometry in the life sciences . Microscope20:203-216.
20.
Fukuhara T., Nishio S., Ono Y., Kawauchi M., Asari S., Ohmoto T. (1994). Induction of Cu, Zn-superoxide dismutase after cortical contusion injury during hypothermia. Brain Res657:333-336.
21.
Ghiabi M., Gallagher GT, Wong DT ( 1992). Eosinophils, tissue eosinophilia and eosinophil-derived transforming growth factor alpha in hamster oral carcinogenesis. Cancer Res52:389-393.
22.
Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW (1994). Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res74:1141-1148.
23.
Hall EJ ( 1988). Radiobiology for the radiologist. Philadelphia: Lippincott, pp. 226-227.
24.
He D., Mu ZM, Le X., Hsieh JT, Pong RC, Chung LW, et al. (1997). Adenovirus-mediated expression of PML suppresses growth and tumorigenicity of prostate cancer cells. Cancer Res57:1868-1872.
25.
Kelner MJ, Bagnell R. (1990). Alteration of endogenous glutathione peroxidase, manganese superoxide dismutase, and glutathione transferase activity in cells transfected with a copper-zinc superoxide dismutase expression vector. Explanation for variations in paraquat resistance. J Biol Chem265:10872-10875.
26.
Lam EW, Zwacka R., Engelhardt JF, Davidson BL, Domann FE Jr, Yan T., et al. (1997). Adenovirus-mediated manganese superoxide dismutase gene transfer to hamster cheek pouch carcinoma cells. Cancer Res57:5550-5556.
27.
Lebovitz RM, Zhang H., Vogel H., Cartwright J. Jr, Dionne L., Lu N., et al. (1996). Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc Natl Acad Sci USA93:9782-9787.
28.
Li JJ, Oberley LW, St. Clair DK, Ridnour LA, Oberley TD (1995). Phenotypic changes induced in human breast cancer cells by overexpression of manganese-containing superoxide dismutase. Oncogene10:1989-2000.
29.
Li N., Oberley TD, Oberley LW, Zhong W. (1998). Overexpression of manganse superoxide dismutase in DU145 human prostate carcinoma cells has multiple effects on cell phenotype . Prostate34:221-233.
30.
Li Y., Huang TT, Carlson EJ, Melov S., Ursell PC, Olson JL, et al. (1995). Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet11:376-381.
31.
Liu R., Oberley TD, Oberley LW (1997). Transfection and expression of MnSOD cDNA decreases tumor malignancy of human oral squamous carcinoma SCC-25 cells. Hum Gene Ther8:585-595.
32.
Lo Yyc, Wong Jms, Cruz TF ( 1996). Reactive oxygen species mediate cytokine activation of c-Jun NH2-terminal kinases. J Biol Chem271:15703-15707.
33.
Marlhens F., Nicole A., Sinet PM (1985). Lowered level of translatable messenger RNAs for manganese superoxide dismutase in human fibroblasts transformed by SV 40. Biochem Biophys Res Commun129:300-305.
34.
McCormick ML, Oberley TD, Elwell JH, Oberley LW, Sun Y., Li JJ (1991). Superoxide dismutase and catalase levels during estrogen-induced renal tumorigenesis, in renal tumors and their autonomous variants in the Syrian hamster. Carcinogenesis12:977-983.
35.
Millikin D., Meese E., Vogelstein B., Witkowski C., Trent J. (1991). Loss of heterozygosity for loci on the long arm of chromosome 6 in human malignant melanoma. Cancer Res51:5449-5453.
36.
Oberley LW, Oberley TD (1986). Free radicals, cancer, and aging. In: Free radicals, aging, and degenerative disease. Johnson JE, Walford R, Harman D, Miquel J, editors. New York: Alan R. Liss, pp. 325-371.
37.
Oberley LW, Bize IB, Sahu SK, Leuthauser SW, Gruber HE (1978). Superoxide dismutase activity of normal murine liver, regenerating liver, and H6 hepatoma. J Natl Cancer Inst61:375-379.
38.
Oberley TD, Oberley LW, Slattery AF, Lauchner LJ, Elwell JH (1990). Immunohistochemical localization of anti-oxidant enzymes in adult Syrian hamster tissues and during kidney development. Am JPathol137:199-214.
39.
Oberley TD, Oberley LW, Slattery AF, Elwell JH (1991). Immunohistochemical localization of glutathione-S-transferase and glutathione peroxidase in adult Syrian hamster tissues and during kidney development. Am J Pathol139:355-369.
40.
Oberley TD, Sempf JM, Oberley MJ, McCormick ML, Muse KE, Oberley LW (1994). Immunogold analysis of anti-oxidant enzymes in human renal cell carcinoma. Virchows Arch424:155-164.
41.
Odukoya 0, Schwartz J., Weichselbaum R., Shklar G. (1983). An epidermoid carcinoma cell line derived from hamster 7,12-dimethylbenz[a]anthracene-induced buccal pouch tumors. J Natl Cancer Inst71:1253-1264.
42.
Picton W., Clark C. (1978). The measurement of histochemically-stained NADP-dependent isocitrate dehydrogenase in the sebaceous glands of hairless hamster. Histochem J10:191-199.
43.
Robertson GP, Coleman AB, Lugo TG ( 1996). Mechanisms of human melanoma cell growth and tumor suppression by chromosome 6. Cancer Res56:1635-1641.
44.
Shklar G. (1972). Experimental oral pathology in the Syrian hamster . Prog Exp Tumor Res16:518-538.
45.
Speir E., Shibutani T., Yu ZX, Ferrans VJ, Epstein SE (1996). Role of reactive oxygen intermediates in cytomegalovirus gene expression and in the response of human smooth muscle cells to viral infection. Circ Res79:1143-1152.
46.
Speir E., Yu ZX, Ferrans VJ, Huang ES, Epstein SE (1998). Aspirin attenuates cytomegalovirus infectivity and gene expression mediated by cyclooxygenase-2 in coronary smooth muscle cells. Circ Res83:210-216.
47.
St. Clair DK, Oberley TD, Muse KE, St. Clair WH (1994). Expression of manganese superoxide dismutase promotes cellular differentiation. Free Radic Biol Med16:275-282.
48.
Stratford-Perricaudet LD, Makeh I., Perricaudet M., Briand P. (1992). Widespread long-term gene transfer to mouse skeletal muscles and heart. J Clin Invest90:626-630.
49.
Sun Y., Li Y., Oberley LW (1988). Superoxide dismutase activity during dimethylhydrazine colon carcinogenesis and the effects of cholic acid and indole. Free Radic Res Comm4:299-309.
50.
Symons MC (1996). Radicals generated by bone cutting and fracture . Free Radic Biol Med20:831-835.
51.
Takahashi H., Hashimoto Y., Kinouchi M., Iizuka H. (1998). Interferon-gamma-dependent induction of manganese superoxide dismutase activity of SV40-transformed human keratinocytes by anti-Fas antibody and by TNF-alpha. J Dermatol Sci16:191-199.
52.
Urano M., Kuroda M., Reynolds R., Oberley TD, St. Clair DK (1995). Expression of manganese superoxide dismutase reduces tumor control radiation dose: gene-radiotherapy. Cancer Res55:2490-2493.
53.
Visner GA, Dougall WC, Wilson JM, Burr IA, Nick HS ( 1990). Regulation of manganese superoxide dismutase by lipopolysaccharide, interleukin-1, and tumor necrosis factor. Role in the acute inflammatory response . J Biol Chem265:2856-2864.
54.
White FH, Gohari K. (1983). Stereological studies of differentiation in hamster cheek pouch epithelium: variations in the volume and frequency of mitochondria . J Anat136:801-819.
55.
White FH, Gohari K., Smith CJ (1981). Histological and ultrastructural morphology of 7,12-dimethylbenz(α)-anthracene carcinogenesis in hamster cheek pouch epithelium. Diagn Histopathol4:307-333.
56.
Wong GH, Goeddel DV (1988). Induction of manganous superoxide dismutase by tumor necrosis factor: possible protective mechanism. Science242:941-944.
57.
Yan T., Oberley LW, Zhong W., St. Clair DK (1996). Manganese-containing superoxide dismutase overexpression causes phenotypic reversion in SV40-transformed human lung fibroblasts. Cancer Res56:2864-2871.
58.
Zhong W., Oberley LW, Oberley TD, Yan T., Domann FE, St. Clair DK (1996). Inhibition of cell growth and sensitization to oxidative damage by overexpression of manganese superoxide dismutase in rat glioma cells. Cell Growth Differ7:1175-1186.
59.
Zhong W., Oberley LW, Oberley TD, St. Clair DK (1997). Suppression of the malignant phenotype of human glioma cells by overexpression of manganese superoxide dismutase. Oncogene14:481-490.
