Hastings L A, Pashko L L, Lewbart M L, Schwartz A G
Department of Microbiology, Temple University Medical School, Philadelphia, PA 19140.
Carcinogenesis. 1988 Jun;9(6):1099-102. doi: 10.1093/carcin/9.6.1099.
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.
脱氢表雄酮是一种天然存在的肾上腺类固醇，在实验室小鼠和大鼠中是一种高效的肿瘤化学预防剂，可抑制自发性乳腺癌以及化学诱导的肺癌、结肠癌、皮肤癌、肝癌和甲状腺癌。脱氢表雄酮可阻断与实验性肿瘤发生有关的三个过程：（i）通过混合功能氧化酶激活致癌物；（ii）12-O-十四烷酰佛波醇-13-乙酸酯刺激中性粒细胞产生超氧阴离子；（iii）12-O-十四烷酰佛波醇-13-乙酸酯刺激小鼠表皮中[3H]胸腺嘧啶核苷的掺入。脱氢表雄酮的所有这些作用很可能是由于葡萄糖-6-磷酸脱氢酶受到抑制以及细胞内NADPH池降低所致。据报道，口服脱氢表雄酮（饲料中含量为0.2%）两周可抑制局部应用12-O-十四烷酰佛波醇-13-乙酸酯后小鼠表皮中前列腺素E2含量的升高。两种合成类固醇，16α-氟-5-雄烯-17-酮和16α-氟-5α-雄甾烷-17-酮，它们是上述肿瘤发生三个过程更有效的抑制剂，并且在抑制小鼠皮肤乳头瘤发展方面也比脱氢表雄酮更有效，在抑制12-O-十四烷酰佛波醇-13-乙酸酯诱导的前列腺素E2方面更具活性。这两种结构类似物也没有与脱氢表雄酮治疗相关的特定副作用，可能会作为癌症化学预防药物应用于人类。
