ANTIHORMONES: THE 20 YEARS BEFORE RU 486

The aim of suppressing hormone activity is almost as old as the word hormone (wrm‘‘’ein: to excite) itself. If a hormone molecule is excitatory for the target cells, then suppression of its effects can be attained by (1) abolition of its production, (2) blockade of its transport from the gland that produces it to target organs, or (3) blockade of its action at the target cell. In the case of small, lipophilic steroids such as P, which act intracellularly, the latter possibility could mean prevention of its entry into potentially responsive cells.

The first of these possibilities, suppression of biosynthesis, seems feasible in humans for some situations. For example, enzymatic inhibitors such as Epostane (4,5-epoxy-17ß-hydroxy-4, 17a-dimethyl-3-oxo-5a-androstane-2-carbonitrile), which inhibits 3ß-hydroxysteroid dehydrogenase, have been tested with some success in abortion (Birgerson and Odlind, 1987; Crooij and Janssens, 1988). An approach that blocks the action of hormones using specific antihormone antibodies—such as antibodies that interact with P in the blood or in target organs (Wang et al., 1989)—does not seem easily applicable to humans. However, an antihormone that operates directly at the receptor level may act more rapidly and be more specific than an inhibitor of a key enzyme involved in the synthesis of many steroids. In fact, the center of hormone action and thus the best molecular target for antihormonal action is the receptor (R) protein molecule, a mandatory element for cellular responses to hormone.2

The image of a receptor portrayed as a lock whose key is the hormone and whose keyhole (in fact a "binding site") can be competitively occupied and consequently put out of order by a false key (an antihormone) has been popular for decades. Because steroids are rigid molecules of well-defined conformation, as the high-affinity binding site of the receptor should be, it seemed logical to expect that a breakthrough in the hormone antagonism field would occur first in the antisteroid field. Initially, steroid receptors were detected by the binding of a traceable (radiolabeled) hormone to tissue extracts. The first of these so-called "radioreceptor" experiments was performed with tritiated estradiol (the natural estrogen) and MER 25, an antiestrogen (Segal and Nelson, 1958) that competed efficiently for radioactive hormone uptake and retention in the uterus (Jensen and Jacobson, 1962). The structure of MER 25 (Figure B1.2) is not that of a steroid. It is a triphenylethylene stilbene derivative with two phenyl rings mimicking rings A and D of

2  

RU 486 can be accommodated between partially unwound, double-stranded DNA bases by computer modeling. Yet the altered conformation of DNA cannot be correlated with the pharmacological properties of antiprogestins (Hendry and Mahesh, 1992).



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