Dehydroepiandrosterone, a naturally occurring adrenal
steroid, is a highly effective
tumor chemopreventive agent in laboratory mice and rats, inhibiting spontaneous
breast cancer and chemically induced
tumors of the lung, colon, skin, liver and thyroid.
Dehydroepiandrosterone blocks three processes that have been implicated in experimental
tumorigenesis: (i)
carcinogen activation through the
mixed-function oxidases, (ii) 12-O-tetradecanoylphorbol-13-acetate stimulation of
superoxide anion production in neutrophils, and (iii) 12-O-tetradecanoylphorbol-13-acetate stimulation of [3H]
thymidine incorporation in mouse epidermis. All of these effects of
dehydroepiandrosterone very likely result from
glucose-6-phosphate dehydrogenase inhibition and a lowering of the
NADPH cellular pool. It is now reported that
oral administration of
dehydroepiandrosterone (0.2% in the diet) for two weeks inhibits the stimulation in
prostaglandin E2 content in mouse epidermis produced by topical application of 12-O-tetradecanoylphorbol-13-acetate. Two synthetic
steroids,
16 alpha-fluoro-5-androsten-17-one and 16 alpha-fluoro-5 alpha-androstan-17-one, which are more potent inhibitors of the above three processes in
tumorigenesis and are also more effective than
dehydroepiandrosterone in inhibiting skin
papilloma development in the mouse, are more active in suppressing
prostaglandin E2 induction by 12-O-tetradecanoyl-phorbol-13-acetate. These two structural analogs, which also lack specific side-effects associated with
dehydroepiandrosterone treatment, may find application as
cancer chemopreventive drugs in humans.