Cross-sectional analysis of intermittent versus chronic caloric restriction in the TRAMP mouse model of prostate cancer Free

B3

Caloric restriction has been shown to prevent the development of cancer in rodent models. With respect to prostate cancer Lobund-Wistar rats subjected to 30% chronic caloric restriction (CCR) developed prostate adenocarcinoma at lower rates (Cancer 64: 686-690, 1989) and had increased survival and lower rates of prostatitis compared to those fed ad libitum (AL) (J Gerontol 45: B52-58, 1990). When CCR and intermittent caloric restriction (ICR) were compared in two mouse transgenic mammary tumor models, tumor incidence was dramatically decreased in ICR mice compared to CCR or ad libitum (AL) fed mice (Cancer Epidemiol Biomarkers Prev 11: 836-843,2002; Nutr Cancer 44: 162-168, 2002). Recently we found that transgenic adenocarcinoma of the mouse prostate (TRAMP) mice undergoing ICR had extended tumor latency and survival times compared to AL or CCR mice (submitted manuscript). Here, we used TRAMP mice to provide a cross-sectional perspective of the protective mechanisms of ICR vs CCR during the development of prostate cancer. Male C57BL6 TRAMP mice were assigned to 1) AL (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), or 3) CCR (fed a diet mixture to match calorie and nutritent intake for each four week ICR cycle which equaled ~75% of AL consumption) groups. Protocols were initiated at 7 wk of age and mice were sacrificed at predetermined ages of 16, 18, 28, 30, 40 and 42 weeks. The two-week separation between time points in a cycle distinguished mice euthanized at the end of a restriction period (ICR-Rest) and those euthanized at the end of a refeeding period (ICR-Refed) within the ICR cohort. As expected, body weights fluctuated in response to calorie intake and were significantly different among the dietary groups (P<0.0001). Final body weights were significantly different among the groups at 16-18 (P<0.0001) and 40-42 (P<0.0054) weeks. A similar trend was found for urogenital tract weights at 16-18 (P<0.0001) and 40-42 (P<0.0003) weeks with ICR-Rest signficantly lower than AL and CCR at both time points. At 16-18 weeks, adenocarcinoma was pathologically confirmed in 0, 12.5, 24 and 33% of the ICR-Rest, ICR-Refed, AL and CCR groups, respectively. At 28-30 weeks, 86% of ICR-Rest mice had adenocarcinoma while all other groups reached 100%; by the 40-42 week time point all mice had confirmed urogenital adenocarcinoma. ICR-Rest mice had significantly lower serum leptin than AL and CCR mice at 16-18 weeks (P<0.05). In contrast ICR mice had the highest serum adiponectin levels across all ages, which reached significance at 28-30 and 40-42 weeks of age. Western blot analysis of prostate tumor tissue for cleaved PARP, PCNA, Bax, Bcl-2 and Bax: Bcl-2 ratio did not show any consistent pattern and no significant differences were found among the groups (P=0.7120, 0.1173, 0.6410, 0.5444 and 0.4698, respectively). Our results show ICR can significantly reduce urogenital tract weight and alter concentrations of serum lepin and adiponectin at various time points in the TRAMP mouse, which may, in part, explain the protective effect ICR. (Support: DAMD17-03-1-0258 and Hormel Foundation)