Mice with the p53 tumor suppressor gene knocked out by gene targeting develop normally but have increased susceptibility to spontaneous tumorigenesis. We have reported that dietary interventions such as calorie restriction (CR; a potent inhibitor of many types of rodent tumors) and the chemopreventive agents, dehydroepiandrosterone (DHEA) and its derivative 16alpha-fluoro-5-androsten-17-one (8354), can offset the increased risk of tumorigenesis resulting from the loss of tumor suppressor function and thus significantly delay tumor development in these genetically susceptible mice. Furthermore, in studies on ex vivo tissues and cells from these mice (studies designed to define the diet-gene interactions underlying efficacious interventions), CR, DHEA and 8354 each suppressed macrophage nitric oxide production, suggesting that a common denominator of interventions which suppress spontaneous tumorigenesis in p53-knockout mice is the ability to decrease oxidative stress. Dietary administration of putative anti-oxidative agents such as piroxicam (a non-steroidal anti-inflammatory drug), genistein (a phytoestrogen), beta-carotene, alpha-tocopherol, 4-hydroxyphenyl-retinamide, and 9-cis retinoic acid failed to confirm this hypothesis. Instead, studies on molecular and immunohistochemical markers of proliferation and apoptosis indicated that CR and DHEA differentially modulate these two determinants of cell number homeostasis. We are also using the differential display reverse transcription PCR technique to identify novel differentially expressed messenger RNAs in tissues from mice on different dietary regimens. Current projects include dietary prevention studies in heterozygous p53-knockout mice, which retain one wild-type allele of the p53 tumor suppressor gene and have a longer latency to tumor development than mice completely lacking p53. The heterozygote may be a good model for the Li-Fraumeni familial cancer syndrome, which in many kindreds has been shown to be associated with a germ-line p53 mutation.
