CHEMOPREVENTION OF SPONTANEOUS TUMORIGENESIS IN NULLIZYGOUS P53-DEFICIENT MICE BY DEHYDROEPIANDROSTERONE AND ITS ANALOG 16-ALPHA-FLUORO-5-ANDROSTEN-17-ONE

Transgenic mice with both alleles of the p53 tumor suppressor gene pro duct 'knocked out' by gene targeting are susceptible to early developm ent of tumors, chiefly lymphomas and sarcomas. Compared with the contr ol group, administration of dehydroepiandrosterone (DHEA) at 0.3% of t he diet to male p53-deficient mice extended their lifespan by delaying death due to neoplasms (from 105 to 166 days on study, P = 0.002), pr imarily by suppressing lymphoblastic lymphoma (from 45 to 6% of neopla stic deaths, P = 0.010). Treatment with a synthetic DHEA analog, 16 al pha-fluoro-5-androsten-17-one (compound 8354), at 0.15% of the diet al so increased lifespan, to 140 days for mice that developed tumors (P = 0.037). The effects of these steroids on lifespan and tumor developme nt did not appear to be strongly related to inhibition of food consump tion and weight gain, in that a group pair-fed with control diet to th e reduced food consumption of the DHEA-treated group developed and die d of the same types of neoplasms at the same rate as the controls fed ad libitum. The chemopreventive effect of these steroids has been prop osed to be due to suppression of DNA synthesis by inhibition of glucos e 6-phosphate dehydrogenase, the rate-limiting enzyme of the pentose p hosphate pathway. Although DHEA and its analog are strong non-competit ive inhibitors of this enzyme in vitro, treatment with DHEA did not de plete cellular nucleotide pools in the liver, as would have been predi cted. The chemopreventive effect of DHEA in this model may be due to s teroid-induced thymic atrophy and suppression of T cell lymphoma, perm itting these mice to survive long enough to develop tumors with longer latency.