Chemoprevention of spontaneous tumorigenesis in nullizygous p53- deficient mice by dehydroepiandrosterone and its analog 16alpha-fluoro- 5-androsten-17-one

Transgenic mice with both alleles of the p53 tumor suppressor gene product'knocked out' by gene targeting are susceptible to early development oftumors, chiefly lymphomas and sarcomas. Compared with the control group,administration of dehydroepiandrosterone (DHEA) at 0.3% of the diet to malep53-deficient mice extended their lifespan by delaying death due toneoplasms (from 105 to 166 days on study, P = 0.002), primarily bysuppressing lymphoblastic lymphoma (from 45 to 6% of neoplastic deaths, P =0.010). Treatment with a synthetic DHEA analog,16alpha-fluoro-5-androsten-17-one (compound 8354), at 0.15% of the dietalso increased lifespan, to 140 days for mice that developed tumors (P =0.037). The effects of these steroids on lifespan and tumor development didnot appear to be strongly related to inhibition of food consumption andweight gain, in that a group pair-fed with control diet to the reduced foodconsumption of the DHEA-treated group developed and died of the same typesof neoplasms at the same rate as the controls fed ad libitum. Thechemopreventive effect of these steroids has been proposed to be due tosuppression of DNA synthesis by inhibition of glucose 6-phosphatedehydrogenase, the rate-limiting enzyme of the pentose phosphate pathway.Although DHEA and its analog are strong non- competitive inhibitors of thisenzyme in vitro, treatment with DHEA did not deplete cellular nucleotidepools in the liver, as would have been predicted. The chemopreventiveeffect of DHEA in this model may be due to steroid-induced thymic atrophyand suppression of T cell lymphoma, permitting these mice to survive longenough to develop tumors with longer latency.