THE FUTURE OF ANTIHORMONE THERAPY - INNOVATIONS BASED ON AN ESTABLISHED PRINCIPLE

Endocrine therapy of mammary and prostate cancer has been established for decades. The therapies available to block sex-hormone-receptor-med iated tumor growth are based on two principles: (i) ligand depletion, which can be achieved surgically, by use of luteinizing-hormone-releas ing hormone analogues or inhibitors of enzymes involved in steroid bio synthesis or by interfering with the feedback mechanisms of sex hormon e synthesis at the pituitary/hypothalamic level; (ii) blockade of sex hormone receptor function by use of antihormones. The antiestrogen tam oxifen, which is the compound of choice for the treatment of mammary c arcinoma, has the drawback of being a partial agonist. A complete bloc kade of estrogen receptor (ER) function can be achieved by a new class of compounds, pure antiestrogens. In contrast to aromatase inhibitors , pure antiestrogens are able to block ER activation by ligands other than estradiol and can also interfere with ligand-independent ER activ ation. In addition to estradiol, progesterone has a strong proliferati ve effect in mammary carcinomas. Antiprogestins are promising new tool s for clinical breast cancer therapy. These compounds clearly need a f unctionally expressed progesterone receptor to block tumor growth, but there is strong experimental evidence that their tumor inhibition is based on more than just progesterone antagonism. The ability of these compounds to induce tumor cell differentiation that leads to apoptosis is unique among all other endocrine therapeutics. In prostate tumors that have relapsed from current androgen-ablation therapies the androg en receptor (AR) is still expressed and, compared to the primary tumor s, its level is often even enhanced. Mutated AR that can be activated by other compounds such as adrenal steroids, estrogens, progestins and even antiandrogens have been detected in recurrent tumors. Thus, rela pse of tumors under the selective pressure of common androgen-ablation therapies can be caused by acquired androgen hypersensitivity and AR activation by ligands other than (dihydro-)testosterone. There is a cl inical need for future compounds that produce a complete blockade of A R activity even in recurrent tumors. Preclinical experiments indicate that combination therapy as well as the extension of endocrine treatme nts to several other tumor entities are promising approaches for furth er developments. Examples are the combination of antiestrogens and ant iprogestins for breast cancer treatment, or the treatment of prostate carcinomas with antiprogestins.