Delayed prostate tumor detection and increased survival time in TRAMP mice by intermittent calorie restriction

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A recent study using transgenic female mice indicated that intermittent calorie restriction (ICR) was more protective than chronic calorie restriction (CCR) with respect to lowering mammary tumor incidence and delaying tumor latency (CEBP, 11: 836, 2002). To examine how these dietary regimes affect prostate cancer development we used both CCR and ICR in the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse. Male C57BL6 TRAMP mice were assigned to 1) ad libitum (free access to AIN-93M diet), 2) ICR (2-wk of 50% caloric restriction using AIN-93M diet with 2x protein, fat, vitamins, and minerals followed by 2-wk of 100% AL consumption of AIN-93M for each corresponding 2-wk), 3) CCR (fed a diet mixture to match calorie and nutritent intake for each four week ICR cycle ~75% of AL consumption) groups. Protocols were initiated at 7 wk of age and mice followed until disease burden necessitated euthanasia or mice reached terminal endpoints of 48 (last of 11 restrictions) or 50 (last of 11 refeedings) wk of age. Prior to euthaniasia, terminal body weights and serum were collected. Final body weights of AL mice were the heaviest followed by ICR-refed, and CCR and ICR-rest weighed the least. GU tract weights and fat pad to carcass ratio followed this pattern. Time to tumor detection was significantly different among the groups (log rank χ² = 8.301, 2 = df, p = 0.016); occurring at median ages of 33, 35 and 38 wk of age for AL, CCR and ICR mice, respectively. There was no statistical difference for age of prostate tumor detection between AL and CCR mice, while ICR mice were significantly older than both AL (p = 0.0066) and CCR (p = 0.0416) mice. No differences were found among the three dietary groups with respect to tumor grade (Pearson χ² = 2.65, df = 6, p = 0.85). A significant difference in survival time was also found among the three groups (log rank χ² = 12.498, df =2, p = 0.009). ICR mice had the longest median survival compared to CCR and AL mice, 46, 40 and 41 wk of age. Forty percent of ICR mice reached their designated terminal end point compared to 27% and 10% for CCR and AL, respectively. Serum leptin, adiponectin, insulin, IGF-1 and leptin to adiponectin ratio were all significantly different among the groups (ANOVA p = 0.0089, 0.0059, 0.0030, 0.0154 and 0.0219). A positive correlation was found between leptin and both fat pad weight (r = 0.5394, p < 0.0001) and final body weight (Peason r = 0.2005, p=0.0066). An inverse correlation was found between adiponectin and final body weight (Pearson r = -0.3249, p < 0.0001). Western blot analyses of tumor tissue showed no significant differences in expression of caspase-3, PARP, PCNA, bax and bcl-2. Results from this study indicate that ICR increases tumor latency and survival time compared to CCR or AL in TRAMP mice. Further analysis of tissues will hopefully identify mechanisms for this effect. (Support: DAMD17-03-1-0258 and Hormel Foundation).