Evaluation of tempol radioprotection in a murine tumor model.
Tempol, a stable nitroxide free radical compound, is an in vitro and in vivo radioprotector. Previous studies have shown that Tempol protects C3H mice against whole-body radiation-induced bone marrow failure. In this study, the radioprotection of tumor tissue was evaluated. RIF-1 tumor cells were implanted in female C3H mice 10 d prior to radiation. Groups of mice were injected intraperitoneally with Tempol (275 mg/kg) or PBS followed 10 min later by a single dose of radiation to the tumor bed. Tumor growth curves generated after 10 and 33.3 Gy doses of radiation showed no difference in growth between the Tempol- and PBS-treated animals. A full radiation dose-response experiment revealed a tumor control dose in 50% of the animals in 30 d (TCD(50/30)) value of 36.7 Gy for Tempol-treated mice and 41.8 Gy for saline-treated mice suggesting no protection of the RIF-1 tumor by Tempol. Tumor pharmacokinetics were done to determine why Tempol differentially protected bone marrow and not tumor cells. Differential reduction of Tempol in the RIF-1 tumor and bone marrow was evaluated with EPR spectroscopy 10, 20, and 30 min after injection. Bioreduction of Tempol to its corresponding hydroxylamine (which is not a radioprotector) occurred to a greater extent in RIF-1 tumor cells compared to bone marrow. We conclude that the differences in radioprotection may result from enhanced intratumor bioreduction of Tempol to its nonradioprotective hydroxylamine analogue. The nitroxides as a class of compounds may provide a means to exploit the redox differences between normal tissues and tumors.
Hahn
S M
SM
Radiation Biology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Sullivan
F J
FJ
DeLuca
A M
AM
Krishna
C M
CM
Wersto
N
N
Venzon
D
D
Russo
A
A
Mitchell
J B
JB
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D011836:Radiation Tolerance / Q000187:drug effects*; D011837:Radiation-Protective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D013113:Spin Labels
D003497:Cyclic N-Oxides; D011837:Radiation-Protective Agents; D013113:Spin Labels; C001803:tempol