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.