CALORIE RESTRICTION DELAYS SPONTANEOUS TUMORIGENESIS IN P53-KNOCKOUT TRANSGENIC MICE

Transgenic mice with both alleles of the p53 tumor suppressor gene (fr equently mutated in human tumors) knocked out by gene targeting provid e a potentially useful tumorigenesis model because these mice rapidly develop spontaneous tumors. To determine whether tumorigenesis in p53- knockout mice is sensitive to experimental manipulation, tumor develop ment in response to calorie restriction (CR; a potent inhibitor of rod ent tumors) was evaluated. Tumor development was monitored for 48 week s in male nullizygous p53-knockout and wild-type littermate mice (28-3 0 per treatment group) fed ad libitum (AL) or restricted to 60% of AL carbohydrate calorie intake. CR:p53-knockout mice (median survival = 2 5 weeks) experienced a delay in tumor onset and subsequent mortality ( P = 0.0002) relative to AL:p53-knockout mice (median survival = 16 wee ks). Tumor development and mortality in wildtype littermates on either diet treatment were <4% through 48 weeks. Cell cycle analyses were pe rformed on splenocytes from p53-knockout mice and wild-type littermate s after 4 weeks of AL feeding or CR (5 per group). The percentage of s plenocytes in S phase of the cell cycle was 3-fold higher for p53-knoc kout mice than wild-type mice (P < 0.001), and CR reduced the percenta ge of S-phase splenocytes in both p53-knockout and wild-type mice (P = 0.012). These data demonstrate that tumor development in p53-knockout mite genetically predisposed to tumors can be delayed by CR (possibly via cell cycle modulation) and suggest that these mice provide a very useful model of spontaneous tumorigenesis.