Nitroxides (such as tempol) which have been used as EPR spin labels have been shown to exhibit superoxide dismutase (SOD) activity and are quite effective agents in protecting cells against a wide variety of oxidative stresses including hydrogen peroxide, superoxide, organic hydroperoxides, redox-cycling chemotherapy drugs, and ionizing radiation. We have demonstrated that Tempol protects both cells in vitro and mice against ionizing radiation. Thus, the nitroxides represent a new class of radiation protectors that may have widespread use in protecting humans against radiation. Importantly, we have shown that tempol does not protect rodent tumor tissue; the mechanism of which we believe involves differential metabolic reduction properties of normal versus tumor tissue. In vivo electron paramagnetic resonance imaging studies in tumor-bearing animals are underway to determine if a differential reduction of nitroxides exists between normal and tumor tissue. We have completed an in vitro study to identify the most efficient nitroxide for protection purposes. Over 110 nitroxides were evaluated in a structure activity relationship study. We have identified 6 nitroxides that afford significantly more radioprotection than tempol (the first nitroxide shown to have radioprotective properties) and have also identified 3 analogs that radiosensitize aerobic cells. These agents will be evaluated and compared with tempol in vivo. We have recently shown that heme proteins exposed to oxidants form highly toxic ferryl moieties and that nitroxides detoxify these toxic species and confer enhanced catalase-like activity to heme species. Since these agents readily penetrate cell membranes, they may be of use in other areas of medical research such as ischemia/reperfusion injury studies, prevention of cataracts, inflammatory processes and aging.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC006387-09
Application #
2464441
Study Section
Special Emphasis Panel (RBB)
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
1996
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Simone, Nicole L; Soule, Benjamin P; Ly, David et al. (2009) Ionizing radiation-induced oxidative stress alters miRNA expression. PLoS One 4:e6377
Ghosh, Manik C; Tong, Wing-Hang; Zhang, Deliang et al. (2008) Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice. Proc Natl Acad Sci U S A 105:12028-33
Soule, Benjamin P; Hyodo, Fuminori; Matsumoto, Ken-Ichiro et al. (2007) The chemistry and biology of nitroxide compounds. Free Radic Biol Med 42:1632-50
Soule, Benjamin P; Hyodo, Fuminori; Matsumoto, Ken-Ichiro et al. (2007) Therapeutic and clinical applications of nitroxide compounds. Antioxid Redox Signal 9:1731-43
Tsai, Mong-Hsun; Cook, John A; Chandramouli, Gadisetti V R et al. (2007) Gene expression profiling of breast, prostate, and glioma cells following single versus fractionated doses of radiation. Cancer Res 67:3845-52
Okajo, Aya; Matsumoto, Ken-ichiro; Mitchell, James B et al. (2006) Competition of nitroxyl contrast agents as an in vivo tissue redox probe: comparison of pharmacokinetics by the bile flow monitoring (BFM) and blood circulating monitoring (BCM) methods using X-band EPR and simulation of decay profiles. Magn Reson Med 56:422-31
Patel, Kinjal; Chen, Yifan; Dennehy, Kathryn et al. (2006) Acute antihypertensive action of nitroxides in the spontaneously hypertensive rat. Am J Physiol Regul Integr Comp Physiol 290:R37-43
Thomas, Douglas D; Ridnour, Lisa A; Espey, Michael Graham et al. (2006) Superoxide fluxes limit nitric oxide-induced signaling. J Biol Chem 281:25984-93
Matsumoto, Ken-Ichiro; Hyodo, Fuminori; Matsumoto, Atsuko et al. (2006) High-resolution mapping of tumor redox status by magnetic resonance imaging using nitroxides as redox-sensitive contrast agents. Clin Cancer Res 12:2455-62
Van Waes, Carter; Chang, Angela A; Lebowitz, Peter F et al. (2005) Inhibition of nuclear factor-kappaB and target genes during combined therapy with proteasome inhibitor bortezomib and reirradiation in patients with recurrent head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 63:1400-12

Showing the most recent 10 out of 20 publications