Brodie A M, Garrett W M, Hendrickson J R, Tsai-Morris C H
Cancer Res. 1982 Aug;42(8 Suppl):3360s-3364s.
Aromatase inhibitor, 4-hydroxyandrostene-3,17-dione (4-OHA), is a highly effective treatment in rats with 7,12-dimethylbenz(a) anthracene-induced hormone-dependent mammary tumors. Over 90% of tumors regress to less than one-half of their original size, and a high proportion regress completely. Treatment of rats with other inhibitors, 4-acetoxyandrostene-3,17-dione and 1,4,6-androstatriene-3,17-dione produce similar results. In comparison with other aromatase inhibitors, the compounds reduced ovarian estrogen secretion in the rat to the same extent as aminoglutethimide, whereas Teslac was without effect. The latter two compounds caused little and no regression of DMBA-induced mammary tumors, respectively. Our recent studies with 4-OHA, 4-acetoxyandrostene-3,17-dione, and 1,4,6-androstatriene-3,17-dione indicate that they interact with aromatase by a two-component mechanism, a rapid competitive inhibition, and a slower enzyme inactivation. Treatment of rats with 4-OHA also caused greater than 80% loss of ovarian aromatase activity in vivo and a reduction in ovarian estrogen secretion, which are maintained for at least 48 hr after injection. Although 4-OHA is cleared rapidly in vivo, the above results suggest that the compound has a sustained effect. Thus, when 7,12-dimethylbenz(a)anthracene-induced tumor-bearing rats were treated with 4-OHA injections on alternate weeks, tumor regression continued to occur during weeks without treatment. The overall regression was similar to that with continuous treatment. 4-OHA is also effective and similar to ovariectomy in rats with hormone-dependent metastatic mammary tumors produced by nitrosomethylurea. Our results indicate that mammary tumor regression induced by 4-OHA is mainly the result of the inhibition of aromatization, although other activities of the compound may also contribute.
芳香化酶抑制剂4-羟基雄甾烯-3,17-二酮（4-OHA）对7,12-二甲基苯并(a)蒽诱导的激素依赖性乳腺肿瘤大鼠是一种高效的治疗药物。超过90%的肿瘤缩小至其原始大小的一半以下，且很大比例的肿瘤完全消退。用其他抑制剂4-乙酰氧基雄甾烯-3,17-二酮和1,4,6-雄甾三烯-3,17-二酮治疗大鼠也产生了类似的结果。与其他芳香化酶抑制剂相比，这些化合物将大鼠卵巢雌激素分泌降低到与氨鲁米特相同的程度，而睾内酯则无此作用。后两种化合物分别对二甲基苯并蒽诱导的乳腺肿瘤几乎没有和完全没有消退作用。我们最近对4-OHA、4-乙酰氧基雄甾烯-3,17-二酮和1,4,6-雄甾三烯-3,17-二酮的研究表明，它们通过双组分机制与芳香化酶相互作用，即快速竞争性抑制和较慢的酶失活。用4-OHA治疗大鼠还导致体内卵巢芳香化酶活性丧失超过80%，卵巢雌激素分泌减少，且注射后至少48小时维持这种状态。尽管4-OHA在体内迅速清除，但上述结果表明该化合物具有持续作用。因此，当对7,12-二甲基苯并(a)蒽诱导的荷瘤大鼠每隔一周注射4-OHA时，在未治疗的几周内肿瘤仍继续消退。总体消退情况与持续治疗相似。4-OHA对亚硝基甲基脲诱导的激素依赖性转移性乳腺肿瘤大鼠也有效，且与卵巢切除效果相似。我们的结果表明，4-OHA诱导的乳腺肿瘤消退主要是抑制芳香化作用的结果，尽管该化合物的其他活性也可能起作用。
