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Studies in our laboratories showed that overexpression of manganese superoxide dismutase (MnSOD) reduced tumor incidence in a multistage skin carcinogenesis mouse model. However, reduction of MnSOD by heterozygous knockout of the MnSOD gene (MnSOD KO) did not lead to an increase in tumor incidence, because a reduction of MnSOD enhanced both cell proliferation and apoptosis. The present study extends our previous studies in the MnSOD KO mice and shows that apoptosis in mouse epidermis occurred prior to cell proliferation (6 versus 24 hours) when treated with tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). To investigate the possibility that a timed administration of SOD following apoptosis but before proliferation may lead to suppression of tumor incidence, we applied a SOD mimetic (MnTE-2-PyP 5+ ) 12 hours after each TPA treatment. Biochemical studies showed that MnTE-2-PyP 5+ suppressed the level of protein carbonyls and reduced the activity of activator protein-1 and the level of proliferating cellular nuclear antigen, without reducing the activity of p53 or DNA fragmentation following TPA treatment. Histologic examination confirmed that MnTE-2-PyP 5+ suppressed mitosis without interfering with apoptosis. Remarkably, the incidence and multiplicity of skin tumors were reduced in mice that received MnTE-2-PyP 5+ before cell proliferation. These results show a novel strategy for an antioxidant approach to cancer intervention. (Cancer Res 2005; 65(4): 1401-5)

Adriamycin (ADR), a potent anti-tumor agent, produces reactive oxygen species (ROS) in cardiac tissue. Treatment with ADR is dose-limited by cardiotoxicity. However, the effect of ADR in the other tissues, including the brain, is unclear because ADR does not pass the blood-brain barrier. Some cancer patients receiving ADR treatment develop a transient memory loss, inability to handle complex tasks etc., often referred to by patients as chemobrain. We previously demonstrated that ADR causes CNS toxicity, in part, via systemic release of cytokines and subsequent generation of reactive oxygen and nitrogen species (RONS) in the brain. Here, we demonstrate that treatment with ADR led to an increased circulating level of tumor necrosis factor-alpha in wild-type mice and in mice deficient in the inducible form of nitric oxide (iNOSKO). However, the decline in mitochondrial respiration and mitochondrial protein nitration after ADR treatment was observed only in wild-type mice, not in the iNOSKO mice. Importantly, the activity of a major mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD), was reduced and the protein was nitrated. Together, these results suggest that NO is an important mediator, coupling the effect of ADR with cytokine production and subsequent activation of iNOS expression. We also identified the mitochondrion as an important target of ADR-induced NO-mediated CNS injury. Keywords: adriamycin-induced chemobrain, central nervous system toxicity, inducible nitric oxide synthase knockout mice, manganese superoxide dismutase, mitochondrial respiration, nitric oxide. Adriamycin (ADR), a prominent member of the anthracycline family, is an important therapeutic agent that has exhibited activity against a wide spectrum of human and experimental animal tumors. It is well established that ADR leads to generation of free radicals, which account for some of the normal tissue damage resulting from cancer treatment (Meredith and Reed 1983;Licinio 1997;Singal et al. 2000). This process may result from the redox cycling capability of anthracycline, its potential to bind nitric oxide (VasquezVivar et al. 1999;Weinstein et al. 2000;Kalivendi et al. 2001;Kalyanaraman et al. 2002) Abbreviations used: ADR, adriamycin; CuZnSOD, copper-zinc superoxide dismutase; DPTA NONOate, dipropylenetriamine NONOate; iNOS, inducible nitric oxide; iNOSKO, mice deficient in the inducible form of nitric oxide; L-NAME, NG-nitro-L-arginine-methyl ester; LPS, lipopolysaccharide; MnSOD, manganese superoxide dismutase; NO, nitric oxide; ONOO -, peroxynitrite; RCR, respiration control ratio; RNS, reactive nitrogen species; RONS, reactive oxygen and nitrogen species; ROS, reactive oxygen species; TNF-a, tumor necrosis factor alpha.

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An irradiation dose of 40 Gy is sufficient to cause female sterility, but has no observed negative effect on male fitness. The results support further development of this approach as a preventative measure against accidental population replacement.