Nitroxides as Protectors against Oxidative StressOur laboratory was first to demonstrate that nitroxides (such as Tempol) are effective antioxidants and protectors against ionizing radiation damage. The mechanism(s) for nitroxide-mediated protection against oxidative stress include superoxide dismutase- and catalase-like activity and radical-radical reactions. However, more recent studies have focused on whether nitroxide treatment impacts gene expression. Cells treated with non-toxic concentrations of several different nitroxide analogues; including a nitroxide incapable of cellular entry (and protection) all exhibit similar patterns of gene expression. A comparison was made of gene expression profiles for MCF7 cells exposed to nitroxides and various forms of oxidative stress (hydrogen peroxide, superoxide, nitric oxide, and ionizing radiation). Interestingly, a small subset of genes related to inflammatory responses was up regulated for all forms of oxidative stress; whereas, the same genes for nitroxide treatment were all down regulated. These studies will provide additional insight into the radio-protective properties of nitroxides, particularly with respect to the differential radioprotection of Tempol toward normal tissues as opposed to tumor. Tempol administered 10 min prior to fractionated radiation treatment does not protect SCC and HT-29 tumor growth; whereas, Tempol administered in the same fashion protects against radiation-induced salivary gland damage. Our lab has made a recent major advancement that can be used to explain this difference. Nitroxides can be used as functional MRI contrast probes allowing for determination of tissue redox status. We have shown that Tempol is reduced in tumor tissue to the non-radioprotective hydroxylamine faster than in salivary gland tissue. Nitroxide based MRI studies thus have the potential to guide to appropriate timing of nitroxide administration to yield maximal radioprotection of normal tissues without protection of tumor. In collaboration with the Radiation Oncology Branch a Phase I clinical trail (first in humans) has been submitted to evaluate Tempol as a functional MRI contrast probe. Since nitroxides readily penetrate cell membranes and are potent antioxidants, they may be of use in other areas of medical research such as ischemia/reperfusion injury studies, prevention of cataracts, inflammatory processes, and aging. Additionally, nitroxide based MRI evaluation may clinical utility in defining the above-mentioned conditions. Lastly, we continue to seek the mechanism of how long-term administration of Tempol (in the food or drinking water) results in dramatic weight reduction and a decrease in spontaneous tumor incidence in mice. Tempol administration also delays the onset of tumors in Atm and p53 deficient mice. We have recently found that systemic levels of IGF-1 are decreased in Tempol treated animals, similar to that observed in caloric restricted animals. These studies will hopefully enable us to better understand the complex cellular/molecular mechanisms of nitroxides that trigger responses important in the antioxidant properties of nitroxides as well as those related to weight and the chemopreventive findings.
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