Two strains of mice were used in this project. Female C3H and CBA mice were exposed to a total body dose of radiation of 3 Gy with or without Tempol supplementation in the animal's food. Immediately following the radiation exposure, animals were be placed on either control or TP-containing food. The groups include: a) no radiation, control food, b) 3 Gy, control food, c) no radiation, TP food, and d) 3 Gy, TP food. For C3H mice, one additional group was added receiving 3 Gy total body irradiation where the administration of the TP containing food was delayed one month post-irradiation. Preliminary data show TP food supplementation after radiation: a) did not alter food consumption compared to animals on a control food diet, b) compared to animals on control food diet, the TP diet resulted in decreased weights in both mouse strains (40% for C3H and 20% for CBA), and c) TP food supplementation post-radiation significantly enhanced the survival of both mouse stains. Median survival values for 0 Gy, 3 Gy, 0 Gy TP, and 3 Gy TP for C3H mice was 706, 434, 764, and 670 days, respectively. For CBA mice median survival values for 0 Gy, 3 Gy, 0 Gy TP, and 3 Gy TP for C3H mice was 901, 660, 939, and 782 days, respectively. The incidence of hematopoietic neoplasms (predominantly lymphomas) was significantly reduced in both mouse strains by TP treatment and both the onset and incidence of solid neoplasms was significantly reduced in CBA mice treated with TP. These preliminary data would encourage further research and development of TP as a chemopreventive agent. The second hypothesis is also being tested that mice protected from lethal total body irradiation by administration of a radioprotector immediately before radiation exposure will experience an elevated risk of cancer induction. Mice were exposed to a total body radiation dose of 10.8 Gy, a radiation dose that results in 100% lethality. Ten minutes prior to the 10.8 Gy exposure the animals will be injected with a radioprotector. The control for this group, another set of animals was exposed to 5.4 Gy total body irradiation. This radiation dose was derived from the radiation dose modification factor (2) when the radioprotector is administered 10 min before total body irradiation. These animals will also be followed for their entire lifespan for tumor induction as outlined above. Preliminary data show that the median survival for mice receiving 0, 5.4 or 10.8 Gy were 706, 460, and 491 days, respectively. There was no difference between the 5.4 and 10.8 Gy groups (p = 0.42);however, the median survival of both irradiated groups was significantly shorter compared to unirradiated mice (p <0.0001). Cancer incidence (hematopoietic plus solid tumors) was similar between the 5.4 and 10.8 Gy groups and was significantly greater than for unirradiated controls. However, the ratio of hematopoietic to solid tumors differed between the two groups, with the 5.4 Gy group having a higher incidence of hematopoietic neoplasms compared to the 10.8 Gy group (1.8 fold). A greater incidence of solid tumors was observed in the 10.8 Gy group. These preliminary results suggest that mice protected from lethal whole body radiation have a shortened lifespan, due in large part, to cancer induction post-radiation compared to unirradiated controls. Lastly studies have been initiated to determine if metabolites in the urine of mice receiving whole body radiation can predict for radiation-induced cancer induction prior to the observation of tumor mass.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010946-04
Application #
8349242
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2011
Total Cost
$321,339
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Cook, John A; Chandramouli, Gadisetti V R; Anver, Miriam R et al. (2016) Mass Spectrometry-Based Metabolomics Identifies Longitudinal Urinary Metabolite Profiles Predictive of Radiation-Induced Cancer. Cancer Res 76:1569-77
Mitchell, James B; Anver, Miriam R; Sowers, Anastasia L et al. (2012) The antioxidant tempol reduces carcinogenesis and enhances survival in mice when administered after nonlethal total body radiation. Cancer Res 72:4846-55