Metabolism of steroid-modifying anticancer agents.

The application of steroid-modifying drugs as a strategy for the treatment of hormone-dependent cancers has gained increasing popularity during the past decade. However, it is important to point out and emphasize that very few of the agents were originally designed for their current application. Most were designed for other purposes, predominantly fertility control (e.g. LHRH agonists and the antiestrogens). Nevertheless, now it is possible to integrate their actions to design rational therapies. There are many reasons for the current interest in antisteroidal drugs. The initial euphoria over the potential ability of combination chemotherapy to cure breast and prostatic carcinoma has proved to be premature. Combination chemotherapy has many severe side-effects which limits patient acceptability, especially if the patient realizes that the likelihood of a cure is remote. In the main, antisteroidal therapies do not have many side-effects and those that do, e.g. aminoglutethimide, are the focus of increased efforts in drug design to produce increased drug specificity. Finally, there is a growing realization that hormone-dependent cancer control with a nontoxic, antisteroidal therapy may be the most acceptable approach currently available for early disease management. Chemotherapy would then be reserved as the final option for treatment. The description of drug metabolism has been central to the development of synthetic LHRH analogs and an understanding of the mode of action of nonsteroidal antiestrogens and antiandrogens. The discovery of steroid synthetic pathways has been essential for the development of the aromatase inhibitors. This whole area of endeavor has now become a major focus of attention for the medicinal chemist. A new generation of agents is entering clinical evaluation which will provide a wealth of valuable information about the successful (or unsuccessful?) methods to control hormone-dependent disease. Since the success or failure of a drug can often depend upon formulation, pharmacokinetics, bioavailability or metabolism, it is our hope that this overview might help solve some of the future problems.