Progress in mechanism-based
cancer prevention research may be facilitated by the use of animal models displaying specific
genetic susceptibilities for
cancer such as mice deficient in the p53 tumor suppressor gene, the most frequently altered gene in human
cancer. We observed in p53-knockout (p53-/-) mice that calorie restriction (CR; 60% of the control group's intake of
carbohydrate energy) increased the latency of spontaneous
tumor development (mostly
lymphomas) approximately 75%, decreased serum
insulin-like growth factor (IGF)-1 and
leptin levels, significantly slowed thymocyte cell cycle traverse and induced apoptosis in immature thymocytes. In heterozygous p53-deficient (p53+/-) mice, CR and 1 d/wk of food deprivation each significantly delayed spontaneous
tumor development (a mix of
lymphomas,
sarcomas and epithelial
tumors) and decreased serum
IGF-1 and
leptin levels even when begun late in life. We have also developed a rapid and relevant p53+/- mouse mammary
tumor model by crossing p53-deficient mice with MMTV-Wnt-1 transgenic mice, and found that CR and 1 d/wk food deprivation significantly increased mammary
tumor latency (greater than twofold) and reduced the mean serum
IGF-1 and
leptin levels to <50% of that of control mice (P < 0.0001). In addition,
fluasterone,
fenretinide and soy each delayed
tumor development but had little effect on
IGF-1 or
leptin levels. We have capitalized on the susceptibility of p53+/- mice to chronic, low dose, aromatic
amine-induced bladder
carcinogenesis to develop a useful model for evaluating
bladder cancer prevention approaches such as
cyclooxygenase-2 inhibition. As demonstrated by these examples, mice with specific (and human-like)
genetic susceptibilities for
cancer provide powerful new tools for testing and characterizing interventions that may inhibit the process of
carcinogenesis in humans.