The naturally occurring adrenal steroid, dehydroepiandrosterone (DHEA), is a highly effective tumor chemopreventive agent in laboratory mice and rats. The DHEA class of steroid inhibits four processes implicated in experimental tumorigenesis, all of which may result from inhibition of glucose-6-phosphate dehydrogenase and lowering of the NADPH and ribose-5- phosphate cellular pools. These include: 1) carcinogen activation through the mixed-function oxidases, 2) tumor promoter stimulation of epidermal DNA synthesis rate and hyperplasia, 3) tumor promoter induction of superoxide (O2-) formation in neutrophils, and 4) tumor promoter stimulation of epidermal prostaglandin E2 levels. Sex hormonal and liver enlarging aide effects are observed following DHEA treatment of laboratory animals, and this could limit the use of DHEA as a cancer chemopreventive drug in humans. We have developed two synthetic analogs, 16alpha-fluoro-5- androsten-17-one (8354) and 16alpha-fluoro-5alpha-androstan-17-one (8356), which do not demonstrate the above side effects and also show enhanced tumor chemopreventive activity in mice in the two-stage skin papilloma system. One of these analogs (8354) has undergone 30-day toxicology evaluation of safety as well as efficacy in inhibiting MNU-induced breast cancer development in female Sprague-Dawley rats and AOM-induced colon cancer in male Fischer rats. Based on positive findings in the above studies, the Chemo-prevention Branch is planning to apply to the F.D.A to undertake Phase I clinical testing. In this application, we are proposing specific experiments that should provide greater insight into the mechanism by which the DHEA class of steroid inhibits tumor promotion. Both in vitro and in vivo data strongly suggest that DHEA inhibits cellular proliferation through a reduction in deoxyribonucleotide synthesis as a consequence of G6PDH inhibition. We will determine the effect of 8354 on the [3H] thymidine labelling index, epidermal thickness and number of nucleated cell layers in mouse epidermis after TPA treatment and also determine the effect of deoxyribonucleoside administration. We will also determine if 8354 inhibits skin papilloma development during the promotion phase in the two- stage skin tumor model and what effect deoxyribonucleoside administration has on tumorigenesis. Pool sizes of the four deoxyribonucleotide triphosphates will also be measured in mouse epidermis topically treated with 8354. In addition, we will also determine the effect of 8354 on the NADPH/NADP ratio in epidermis and on the level of 6-phosphogluconate.
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