Authors
Perkins SN. Hursting SD. Haines DC. James SJ. Miller BJ. Phang JM.
Institution
Laboratory of Nutritional and Molecular Regulation, SAIC, National Cancer
Institute-Frederick Cancer Research and Development Center, MD 21702-1201,
USA.
Title
Chemoprevention of spontaneous
tumorigenesis in nullizygous p53-deficient mice by dehydroepiandrosterone and
its analog 16alpha-fluoro-5-androsten-17-one.
Source
Carcinogenesis. 18(5):989-94, 1997 May.
Abstract
Transgenic mice with both alleles of the p53 tumor suppressor gene product
'knocked out' by gene targeting are susceptible to early development of
tumors, chiefly lymphomas and sarcomas. Compared with the control group,
administration of dehydroepiandrosterone (DHEA) at 0.3% of the 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), primarily by suppressing
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 diet also increased lifespan, to 140 days
for mice that developed tumors (P = 0.037). The effects of these steroids on
lifespan and tumor development did not appear to be strongly related to
inhibition of food consumption and weight gain, in that a group pair-fed with
control diet to the reduced food consumption of the DHEA-treated group
developed and died of the same types of neoplasms at the same rate as the
controls fed ad libitum. The chemopreventive effect of these steroids has
been proposed to be due to suppression of DNA synthesis by inhibition of
glucose 6-phosphate dehydrogenase, the rate-limiting enzyme of the pentose
phosphate pathway. Although DHEA and its analog are strong non-competitive
inhibitors of this enzyme in vitro, treatment with DHEA did not deplete
cellular nucleotide pools in the liver, as would have been predicted. The
chemopreventive effect of DHEA in this model may be due to steroid-induced
thymic atrophy and suppression of T cell lymphoma, permitting these mice to
survive long enough to develop tumors with longer latency.