Therapeutic and Clinical Applications of Nitroxide Compounds

Abstract

Nitroxide compounds have been used for many years as biophysical tools, but only during the past 15-20 years have the many interesting biochemical interactions been discovered and harnessed for therapeutic applications. By modifying oxidative stress and altering the redox status of tissues, nitroxides have the ability to interact with and alter many metabolic processes. This interaction can be exploited for therapeutic and research use, including protection against ionizing radiation, as probes in functional magnetic resonance imaging, cancer prevention and treatment, control of hypertension and weight, and protection from damage resulting from ischemia/reperfusion injury. Although much remains to be done, many applications have been well studied, and some are presently being tested in clinical trials. The therapeutic and research uses of nitroxides are reviewed here, with a focus on the progress from initial development to modern, state-of-the art trials.

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…Further experiments with animals bearing radiation-induced fibrosarcoma RIF-1 tumor cells, in which Tempol was injected 10 min before radiation, indicated that, fortunately, it does not protect tumor cells. The data suggest that, in the hypoxic tumor environment, Tempol is reduced and is thus inactive, whereas it is oxidized in surrounding normal tissue (297). Tempol also decreased radiation-related hair loss and increased hair recovery in guinea pigs and in 12 patients.…”

“…Tempol remained on the scalp for *30-45 min each day and was well tolerated (296). Tempol also decreased radiationinduced salivary hypofunction with C3H mice (297). A few anticancer studies indicate that nitroxides can affect tumor redox status and thus affect apoptotic and proliferative pathways.…”

“…A detailed review of the protective effects of nitroxides was published by Soule et al (296,297) and is briefly summarized here. Nitroxides were shown to be radioprotective when given IP to mice before radiation.…”

“…Tempol was injected at 275 mg=kg, 5-10 min before radiation exposure (147,296). In vitro, reduced Tempol (hydroxylamine) was not efficient in protecting Chinese hamster cells against radiation, whereas Tempol was most effective at 50 mM levels (297). Further experiments with animals bearing radiation-induced fibrosarcoma RIF-1 tumor cells, in which Tempol was injected 10 min before radiation, indicated that, fortunately, it does not protect tumor cells.…”

“…With ataxia telangiectasia (Atm-deficient cancer prone mice), tumorigenicity was ameliorated (281,297); the results were attributed, at least in part, to the modulation of redoxsensitive signaling pathways. Increased apoptosis and decreased neovascularization were observed in a Chinese hamster ovary model, MCF-7 breast cancer, p53-negative leukemia cells, and a murine xenograft glioma model, rendering Tempol a prospective anticancer drug (297).…”