Ratko T A, Detrisac C J, Mehta R G, Kelloff G J, Moon R C
Laboratory of Pathophysiology, IIT Research Institute, Chicago, Illinois 60616.
Cancer Res. 1991 Jan 15;51(2):481-6.
The chemopreventive efficacy of p.o. administered dehydroepiandrosterone (DHEA), DHEA plus N-(4-hydroxyphenyl)retinamide (4-HPR), or 16 alpha-fluoro-5-androsten-17-one (DHEA analogue 8354) was examined in rats treated with N-methyl-N-nitrosourea (MNU; 50 mg/kg body weight, i.v.) at 50 days of age. Semipurified diet (AIN-76A) containing each steroid alone, or DHEA plus 4-HPR, was administered during initiation (-1 week to +1 week post-MNU), promotion/progression (+1 week post-MNU to termination), or both phases (-1 week post-MNU to termination) of the carcinogenic process. Neither DHEA nor DHEA analogue 8354 (0.2%, w/w) significantly affected the initiation of mammary cancer when administered alone; however, DHEA (0.2%, w/w) plus 4-HPR (1 mmol/kg diet) significantly reduced cancer multiplicity (26%) when given during initiation. All three treatments were strongly effective when given during promotion/progression, significantly reducing mammary cancer multiplicity by 77% (DHEA), 84% (DHEA/4-HPR), and 66% (DHEA analogue 8354), relative to carcinogen controls. Cancer incidence was significantly inhibited by DHEA (33% inhibition) and DHEA/4-HPR (24% reduction) during promotion/progression. However, the most effective chemopreventive treatment encompassed both phases of carcinogenesis. Thus, under these conditions, DHEA (0.2% or 0.1%, w/w) reduced cancer incidence (52% and 32% reductions, respectively) and multiplicity (91% and 86% reductions, respectively). Further reduction in mammary cancer incidence was observed in animals that received DHEA (both doses) plus 4-HPR (1 and 0.5 mmol/kg diet, respectively). DHEA analogue 8354 (0.2% or 0.1%, w/w) given for the duration of the study reduced only cancer multiplicity (61% and 56% reductions, respectively). Tumor-related mortality was significantly lower in rats that received long-term treatment with DHEA or DHEA/4-HPR, when compared with carcinogen controls. Except for a slight, but significant, postcarcinogen decrease in the mean body weights of rats treated concomitantly with DHEA (plus or minus 4-HPR) and MNU, additional gross manifestations of steroid-induced toxicity were not observed.
在50日龄用N-甲基-N-亚硝基脲（MNU；50mg/kg体重，静脉注射）处理的大鼠中，检测了口服脱氢表雄酮（DHEA）、DHEA加N-(4-羟基苯基)视黄酰胺（4-HPR）或16α-氟-5-雄烯-17-酮（DHEA类似物8354）的化学预防效果。在致癌过程的起始阶段（MNU处理后-1周至+1周）、促进/进展阶段（MNU处理后+1周至处死）或两个阶段（MNU处理后-1周至处死），给予单独含有每种甾体的半纯化饮食（AIN-76A），或DHEA加4-HPR。单独给予DHEA或DHEA类似物8354（0.2%，w/w）时，对乳腺癌的起始均无显著影响；然而，起始阶段给予DHEA（0.2%，w/w）加4-HPR（1mmol/kg饮食）可显著降低癌灶数量（降低26%）。在促进/进展阶段给予所有三种处理均有强效，相对于致癌物对照组，DHEA、DHEA/4-HPR和DHEA类似物8354分别使乳腺癌灶数量显著减少77%、84%和66%。在促进/进展阶段，DHEA（抑制33%）和DHEA/4-HPR（降低24%）显著抑制了癌症发生率。然而，最有效的化学预防处理涵盖致癌作用的两个阶段。因此，在这些条件下，DHEA（0.2%或0.1%，w/w）分别降低了癌症发生率（分别降低52%和32%）和癌灶数量（分别降低91%和86%）。在接受DHEA（两种剂量）加4-HPR（分别为1和0.5mmol/kg饮食）的动物中，观察到乳腺癌发生率进一步降低。在整个研究期间给予DHEA类似物8354（0.2%或0.1%，w/w）仅降低了癌灶数量（分别降低61%和56%）。与致癌物对照组相比，长期接受DHEA或DHEA/4-HPR处理的大鼠的肿瘤相关死亡率显著较低。除了同时接受DHEA（加或不加4-HPR）和MNU处理的大鼠在致癌物处理后平均体重有轻微但显著的降低外，未观察到甾体诱导毒性的其他明显表现。
