Aminoglutethimide and ketoconazole: historical perspectives and future prospects.

Aminoglutethimide and ketoconazole, although originally developed as an anticonvulsant and antifungal agent respectively, have both been used to suppress steroid biosynthesis in patients with hormone-sensitive cancer. Aminoglutethimide inhibits several enzymes involved in the synthesis of corticosteroids as well as the aromatase enzyme which converts androgens to oestrogens. About one third of patients with breast cancer show objective improvement with aminoglutethimide, and it may also be of use in the treatment of adrenal carcinoma. However, its toxicity, and the need for concomitant cortisol replacement, severely limit its usefulness. Ketoconazole also inhibits several steroidogenic enzymes, notably C17,20-lyase, and has been used to treat carcinoma of the prostate. Again however, its toxicity and limited efficacy limit its value, although it may be useful in the treatment of certain endocrine conditions such as precocious puberty. Several aromatase inhibitors similar in structure to aminoglutethimide have been developed in an attempt to create more selective and efficient inhibitors. Some of these compounds have been tested in animals but none have as yet been subjected to clinical trials. Attempts to produce imidazole inhibitors of steroidogenesis are less advanced, although one compound (CGS 16949A) has been reported to be a more selective and potent aromatase inhibitor than aminoglutethimide. Selective and effective compounds could be of great value in the treatment of hormone-sensitive carcinoma.