David Henderson

New steroids with antiprogestational and antiglucocorticoid activities

A number of 11-substituted 19-norsteroids with inverse configuration at C-13 were synthesized. 11 beta-Aryl compounds in this series were found to possess antiprogestational and antiglucocorticoid activities.

1-Methyl-1,4-androstadiene-3,17-dione (SH 489): characterization of an irreversible inhibitor of estrogen biosynthesis.

1-Methyl-1,4-androstadiene-3,17-dione (SH 489) was characterized as a competitive and irreversible inhibitor of human placental aromatase. The compound and the principal predicted metabolites show no endocrinological side effects suggesting that SH 489 should be suitable as a prototype drug for treatment of estrogen-dependent disease states.

Aromatase inhibitors: Their biochemistry and clinical potential

It has been proposed that one of the endocrinological factors in the pathogenesis of benign prostatic hyperplasia is estrogen stimulation of stromal growth. Current clinical experience with anti-estrogenic compounds indicates that, in the case of mammary carcinoma, aromatase inhibitors provide a viable alternative to estrogen receptor antagonists for treatment of the disease. It is proposed that inhibitors of estrogen biosynthesis could likewise provide a non-invasive therapy for benign prostate disease. Some aspects of the activity of known aromatase inhibitors as substrates for enzymes of steroid metabolism and their potential relevance to the pharmacology of the compounds are discussed.

Aromatase inhibitors and benign prostatic hyperplasia

A growing amount of evidence implies that estrogens may play a role together with androgens in the genesis of benign prostatic hyperplasia (BPH) in man. We review here some of this evidence together with advances made in characterizing inhibitors of estrogen biosynthesis (aromatase inhibitors). It is proposed that aromatase inhibitors may find application in non-surgical treatment of BPH.

Co-operation of progestational steroids with epidermal growth factor in activation of gene expression in mammary tumor cells

The progesterone receptor belongs to a class of ligand binding transcription factors that regulate transcription by interacting with specific DNA sequences on hormone regulated genes. In human mammary tumor T47D cells that contain both progesterone and epidermal growth factor (EGF) receptors, the progestin-induced transactivation at various hormone regulated promoters is enhanced by EGF. The effect of EGF is rapid and does not require new protein synthesis. EGF treatment does not alter the DNA binding activity of the progesterone receptor nor does it affect the total ligand-dependent phosphorylation of this receptor. These results suggest that EGF enhances the transactivation property of the progesterone receptor through mechanisms other than those involving a direct interaction of this receptor with its cognate binding sites.

Estrogens and benign prostatic hyperplasia: The basis for aromatase inhibitor therapy

Benign prostatic hyperplasia is generally regarded as being a hormone-dependent disorder. The inductive action of stromal elements on the glandular epithelium and the demonstrable estrogen sensitivity of the stroma suggest that estrogens may play a role in the etiology of prostatic hyperplasia. This hypothesis forms the theoretical basis for the proposed use of aromatase inhibitors in treatment of this disorder.

Synthesis of ENT-17-(prop-1-ynyl-17β-hydroxy-11β-(4-(N,N-dimethylamino) -phenyl)-4,9-estradien-3-one, the antipode of RU — 38 486

The title compound was synthesized and tested for its biological activities. It showed neither antiprogesterone nor antiglucocorticoid properties.

The regulation of expression of mouse mammary tumor virus DNA by steroid hormones and growth factors.

Mouse mammary tumor virus (MMTV) expression is associated with hyperplastic alveolar growth and subsequent development of mammary cancers in the mouse. The expression of this virus is also controlled by factors involved in the normal proliferation and differentiation of the mammary epithelium. During pregnancy when the mammary gland undergoes massive proliferation, MMTV expression is increased. Steroid hormones and growth factors that play an important role in the proliferation of mammary gland cells are responsible for the increased MMTV expression. In sarcomatous transformation of mouse mammary epithelial cells, MMTV expression is repressed. This repression is due to negative control of MMTV expression by transforming growth factor-beta (TGF beta). This growth factor is produced in high amounts when mammary epithelial cells progress into the transformed state. The expression of MMTV is therefore under multiple control by steroid hormones and growth factors.