The antioxidant tempol reduces carcinogenesis and enhances survival in mice when administered after nonlethal total body radiation

Abstract

There is significant interest in the development of agents that can ameliorate radiation damage after exposure to radiation has occurred. Here we report that chronic supplementation of the antioxidant Tempol in the diet of mice can reduce body weight without toxicity, decrease cancer, and extend survival when administered after nonlethal total body radiation (TBI). These effects were apparent in two different strains of mice (C3H, CBA) exposed to TBI (3 Gy). Notably, delaying administration of the Tempol diet one month after TBI could also enhance survival. Tempol reduced the incidence of hematopoietic neoplasms (lymphomas) in both strains, whereas both the onset and incidence of nonhematopoietic neoplasms were reduced in CBA mice. These results encourage further study of Tempol as a chemopreventive, to reduce the incidence of radiation-induced second malignancies after a course of definitive radiation therapy. Tempol may also find applications to reduce the risk of cancers in populations exposed to nonlethal radiation due to nuclear accidents or terrorist attacks.

Figure 1

Average weight/mouse (grams) of various groups of CBA (A) and C3H (C) mice as a function of time. Average food consumption (grams) per mouse/day for the various groups of CBA (B) and C3H (D) mice.

Figure 2

A) Kaplan-Meier survival plots for CBA mice. Mice were exposed to either 0 or 3 Gy TBI with Tempol food supplementation initiated immediately after radiation and maintained throughout the lifespan. Statistics using log rank analysis of the survival curves: 0 Gy C vs 0 Gy T (p = 0.91); 3 Gy C vs 3 Gy T (p < 0.003). B) Cumulative incidence of deaths for various groups of CBA mice shown in A: hematopoietic neoplasms (B, C), non-HN (D, E), and non-cancer deaths (F, G).

Figure 3

A) Kaplan-Meier survival plots for C3H mice. Mice were exposed to either 0 or 3 Gy TBI with Tempol food supplementation initiated immediately after radiation and maintained throughout the lifespan. Statistics using log rank analysis of the survival curves: 0 Gy C vs 0 Gy T (p = 0.06); 0 Gy C vs 3 Gy C (p < 0.001); 0 Gy T vs 3 Gy T (p < 0.001); 3 Gy C vs 3 Gy T (p < 0.001); 3 Gy C vs 3 Gy T Delayed (p < 0.001); 3 Gy T vs 3 Gy T Delayed (p = 0.07). B) Cumulative incidence of deaths for various groups of C3H mice shown in A: hematopoietic neoplasms (B, C), non-HN (D, E), and non-cancer deaths (F, G).

Figure 4

Gene expression patterns in muscle, liver, and brain tissues taken from C3H mice on control or Tempol supplemented diets for 2 weeks or 2 months. Expression patterns were analyzed by hierarchical clustering monitoring 2-fold gene changes in the tissues. The cluster maps were normalized to the 2 week control diet mice. (gene expression: green, up-regulated; red, down-regulated)