Potential use of nitroxides in radiation oncology.
The identification of radioprotectors is an important goal for those involved in radiation oncology and for those interested in the investigation of the mechanisms of radiation cytotoxicity. Recently, a new class of in vitro and in vivo radioprotectors, the nitroxides, has been discovered. The nitroxides are low-molecular-weight stable free radicals which are freely membrane permeable and which have been shown to act as superoxide dismutase mimics. Further investigation of these compounds has shown that a water-soluble nitroxide, Tempol, protects cultured Chinese hamster V79 cells from the cytotoxicity caused by superoxide, hydrogen peroxide, and t-butyl hydroperoxide. Tempol and five other water-soluble nitroxides have also been shown to protect V79 cells against radiation-induced cytotoxicity. Potential mechanisms of protection by the nitroxides include oxidation of reduced transition metals, superoxide dismutase-like activity, and scavenging of oxy- and carbon-based free radicals. In vivo studies reveal that Tempol protects C3H mice from the lethal effects of radiation with a dose causing 50% lethality within 30 days of 9.97 Gy and 7.84 Gy in Tempol-treated and saline-treated mice, respectively, and a dose modification factor of 1.3. The nitroxides represent a new class of non-thiol radioprotectors which may also have application as general antioxidants. Additional work is necessary to screen other nitroxides for in vivo radioprotection and toxicity as well as to fully evaluate the extent to which these compounds protect tumors.
Hahn
S M
SM
Radiation Biology Section, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Krishna
C M
CM
Samuni
A
A
DeGraff
W
W
Cuscela
D O
DO
Johnstone
P
P
Mitchell
J B
JB
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D006224:Cricetinae; D003412:Cricetulus; D003497:Cyclic N-Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D003603:Cytotoxins / Q000633:toxicity*; D004307:Dose-Response Relationship, Radiation; D006861:Hydrogen Peroxide / Q000633:toxicity; D051379:Mice; D008809:Mice, Inbred C3H; D010545:Peroxides / Q000633:toxicity; D011837:Radiation-Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D013113:Spin Labels; D013481:Superoxides / Q000633:toxicity; D020122:tert-Butylhydroperoxide
D003497:Cyclic N-Oxides; D003603:Cytotoxins; D010545:Peroxides; D011837:Radiation-Protective Agents; D013113:Spin Labels; D013481:Superoxides; D020122:tert-Butylhydroperoxide; D006861:Hydrogen Peroxide; C001803:tempol