Immunolocalization and Adenoviral Vector-mediated Manganese Superoxide Dismutase Gene Transfer to Experimental Oral Tumors

Abstract

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[alpha]anthracene. Animals were killed at periodic intervals, and cheek 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.

Manganese superoxide dismutase deficiency enhances cell turnover via tumor promoter-induced alterations in AP-1 and p53-mediated pathways in a skin cancer model

“…Numerous studies in cultured cells suggested that MnSOD, a primary antioxidant enzyme, might function as a new type of tumor suppressor gene (Church et al, 1993;Saord et al, 1994;Urano et al, 1995;Li et al, 1995Li et al, , 1998Yan et al, 1996;Liu et al, 1997;Lam et al, 1997;Amstad et al, 1997;Zhong et al, 1997). We have previously studied the potential tumor-suppressor function of MnSOD in vivo by using a two-stage carcinogenesis model (Zhao et al, 2001b).…”

Decreased Expression of Manganese Superoxide Dismutase in Transformed Cells Is Associated with Increased Cytosine Methylation of the SOD2 Gene

“…Abnormal cytosine methylation has been shown to be associated with transcriptional inactivation of a number of tum or suppressor genes, including Rb, p16, E-cadherin, and ER (Stirzaker et al, 1997, Merlo et al, 1995, Yoshiura et al, 1995, Ottaviano et al, 1994. A growing body of literature indicates that the SOD2 gene product, MnSOD, exerts a novel tum or-suppressing effect in malignant cells (Zhong et al, 1997;Lam et al, 1997;Yan et al, 1996). Although SOD2 transcription can be induced in response to various stimuli, including oxidants, tumor necrosis factor-alpha, interleukin-1-alph a, and radiation (Visner et al, 1990;Akashi et al, 1995), little is known about the mechanisms governing its constitutive expression in normal and transform ed cells.…”

“…Indeed, diminished MnSOD expression has been reported in cancers from a variety of cell types and etiologies (Oberley et al, 1978;Marlens et al, 1985;McCormick et al, 1991). In many cancer cell lines in culture, enforced expression of MnSOD by transfection of SOD2 cDNA has led to reversal of the malignant phenotype (Zhong et al, 1997;Lam et al, 1997;Yan et al, 1996). These observations have led to the supposition that SOD2 is a new kind of suppressor gene whose dim inished expression participates in driving malignant progression (Bravard et al, 1992).…”

Manganese superoxide dismutase overexpression inhibits the growth of androgen-independent prostate cancer cells

“…where L is the longest dimension of the tumor in mm and W is the shortest dimension of the tumor in mm (Zhong et al, 1996;Lam et al, 2000). When the tumors reached a predetermined volume of 1000 mm 3 , animals were euthanized by CO 2 asphyxiation and this was considered the time of killing.…”