THIS PROJECT WILL USE MALE AND FEMALE TRP53?P/?P MICE OBTAINED FROM AN IN-HOUSE BREEDING COLONY AT THE UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES (UAMS) WITH TRP53?P/?P BREEDERS PROVIDED BY DR. BALMAIN (UCSF). A TOTAL OF 366 TRP53?P/?P MICE WILL BE GENERATED AND USED THE TWO SPECIFIC AIMS AS FOLLOWS: SPECIFIC AIM 1: DETERMINE THE EFFICACY OF ?-TOCOTRIENOL AS A COUNTERMEASURE AGAINST MIXED CHARGED PARTICLE RADIATION-INDUCED CARCINOGENESIS. AT THE AGE OF 4 MONTHS A TOTAL OF 210 MICE WILL BE TRANSPORTED TO BNL. MICE WILL BE EXPOSED TO SIMULATED GCR (5 ONCE-A-DAY FRACTIONS OF 0.15 GY FOR 5 CONSECUTIVE DAYS) OR SHAM-IRRADIATION AT NSRL. ?-TOCOTRIENOL WILL BE OBTAINED FROM A NATURAL SOURCE AS ROUTINELY PURIFIED BY GUANGRONG ZHENG PHD (UNIVERSITY OF FLORIDA). MICE WILL BE ADMINISTERED ?-TOCOTRIENOL ONCE DAILY BY SUBCUTANEOUS INJECTION (50 MG/KG BODYWEIGHT) 24 HOURS BEFORE EACH RADIATION FRACTION. AFTER ?- TOCOTRIENOL ADMINISTRATION AND RADIATION ARE COMPLETE THE MICE WILL BE TRANSPORTED TO COLORADO STATE UNIVERSITY (CSU) FOR 18-MONTH FOLLOW-UP. MICE WILL BE EXAMINED DAILY FOR THE PRESENCE OF TUMORS USING ROUTINE PROTOCOLS IN THE LABORATORY OF MICHAEL WEIL PHD. MICE WILL BE HUMANELY EUTHANIZED IF PALPABLE TUMORS ARE PRESENT OR THE ANIMALS ARE MORIBUND BASED ON PRE-DETERMINED CRITERIA. ALL OTHER MICE WILL BE EUTHANIZED AT 18 MONTHS AFTER IRRADIATION. ANIMALS WILL BE NECROPSIED UPON EUTHANASIA AND ORGAN SITE AND NUMBER OF TUMORS RECORDED. OVERALL TUMOR BURDEN AND TIME TO OCCURRENCE WILL BE ANALYZED. SAMPLES OF TUMORS WILL BE COLLECTED FOR HISTOPATHOLOGICAL VERIFICATION BY A VETERINARY PATHOLOGIST WHO ROUTINELY EXAMINES TUMOR SAMPLES IN STUDIES ON SPACE RADIATION CARCINOGENESIS AT CSU. AN ADDITIONAL GROUP OF 60 TRP53?P/?P MICE WILL BE TRANSPORTED TO BNL AND EXPOSED TO RADIATION AT NSRL AS DESCRIBED ABOVE. THESE MICE WILL BE USED TO OBTAIN PLASMA SAMPLES AT 4 8 AND 24 HOURS AFTER ?-TOCOTRIENOL ADMINISTRATION ON DAYS 1 3 AND 5 OF IRRADIATION. SAMPLES WILL BE USED TO MEASURE CONCENTRATIONS OF ?-TOCOTRIENOL WITH LIQUID CHROMATOGRAPHY (HPLC). SPECIFIC AIM 2: DETERMINE THE EFFICACY OF ?-TOCOTRIENOL AS A COUNTERMEASURE AGAINST MIXED CHARGED PARTICLE RADIATION-INDUCED GENOMIC INSTABILITY. AT THE AGE OF 4 MONTHS A TOTAL OF 96 TRP53?P/?P MICE WILL BE TRANSPORTED TO BNL AND EXPOSED TO RADIATION AT NSRL AS DESCRIBED ABOVE. AFTER RADIATION IS COMPLETE THE MICE WILL BE TRANSPORTED TO THE LABORATORY OF RUPAK PATHAK PHD AT UAMS. AT 1 WEEK AND 4 WEEKS AFTER IRRADIATION MICE WILL BE USED TO ASSESS CHROMOSOMAL ABERRATION IN BONE MARROW CELLS WITH MULTIPLE FLUORESCENCE IN SITU HYBRIDIZATION (MFISH) AND SPECTRAL KARYOTYPING (SKY) USING ROUTINE PROTOCOLS IN THE PATHAK LABORATORY.