Hursting SD, Perkins SN, Phang JM:
Calorie restriction delays spontaneous tumorigenesis in p53-knockout
transgenic mice.
Proceedings of the National Academy of Sciences of the United States of
America 1994 Jul 19;91(15):7036-40
ABSTRACT
Transgenic mice with both alleles of the p53 tumor suppressor gene
(frequently mutated in human tumors) knocked out by gene targeting
provide 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 development in response to calorie restriction
(CR; a potent inhibitor of rodent tumors) was evaluated. Tumor
development was monitored for 48 weeks in male nullizygous
p53-knockout and wild-type littermate mice (28-30 per treatment
group) fed ad libitum (AL) or restricted to 60% of AL carbohydrate
calorie intake. CR:p53-knockout mice (median survival = 25 weeks)
experienced a delay in tumor onset and subsequent mortality (P =
0.0002) relative to AL:p53-knockout mice (median survival = 16
weeks). Tumor development and mortality in wild-type littermates on
either diet treatment were < 4% through 48 weeks. Cell cycle
analyses were performed on splenocytes from p53-knockout mice and
wild-type littermates after 4 weeks of AL feeding or CR (5 per
group). The percentage of splenocytes in S phase of the cell cycle
was 3-fold higher for p53-knockout mice than wild-type mice (P <
0.001), and CR reduced the percentage of S-phase splenocytes in both
p53-knockout and wild-type mice (P = 0.012). These data demonstrate
that tumor development in p53-knockout mice 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.
