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 6-alpha-fluoro-5-androsten-17-one (8354, fluasterone) 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. In studies with ex vivo tissues and cells from these mice (studies designed to define the diet-gene interactions underlying efficacious interventions), DHEA and 8354 were found to modulate thymocyte maturation at an early stage. Additional studies with in vitro thymocytes and a murine T cell hybridoma cell line have refined our understanding of the effects of steroids in this cell type, in particular how they modulate progression of the cell cycle and induce cell death.Ongoing projects include dietary prevention studies in heterozygous p53-deficient 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. We found that CR appears to be effective in male heterozygous p53- deficient mice even when started at a much older age. The effect of DHEA in these animals, if any, was less clear. However, in older female heterozygous p53-deficient mice, compound 8354 (which lacks the harmful androgenic side-effects of DHEA) was effective in delaying development of certain sarcomas. We have also found that heterozygous p53-deficient mice are more susceptible to lymphomas induced by the carcinogen N- methyl-N-nitrosourea than wild-type mice. However, this increased susceptibility did not appear to be due to increased mutation of the remaining wild-type p53 allele, as rates of p53 mutation were similarly low in both groups. About half of the lymphomas from the heterozygous p53-deficient mice lost the remaining wild-type p53 allele, however. K- ras mutations were frequent in lymphomas from both p53-deficient and wild-type mice. We are also testing CR and compound 8354 in female Wnt- 1 p53-deficient bitransgenic mice. These mice inevitably develop mammary tumors, and our interventions appear to be even more effective against these highly proliferative tumors. - Cancer Prevention, Lymphoma, Thymus, Transgenic Mice, Tumor Suppressor, sarcoma, K-ras, N- methyl-N-nitrosourea, Mammary tumorigenesis, p, Tumor Suppressor, hormones,
