Development of new drugs for endocrine tumour chemotherapy

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The aim of our investigations is the development of new substances for endocrine treatment of hormone-dependent mammary carcinomas. Figure 1 shows in diagrammatic form some of the factors involved in the regulation by endocrine glands of hormone-dependent breast cancer and the different target points for endocrine treatment. Only the influence of oestrogens will be considered here and the co-operative effect of other hormones is excluded. There are three different possibilities of inhibiting the growth of mammary tumours and their metastases at a hormonal level: withdrawal ofoestrogens, administration of high doses of hormones, or antagonism of endogenous oestrogens. A decrease of the oestrogen level is accomplished by ablation; primarily by removal of still functioning ovaries, but also by adrenalectomy and or hypophysectomy. The biosyntheses of oestrogens can be inhibited first of all in the central nervous system. Presently, analogues of the gonadotropin releasing hormone that are active against tumours of the prostate are being tested for their activity against hormone-dependent breast cancer (3). In the periphery oestrogen synthesis in the adrenal gland is important since usually the ovaries have been removed or their function has ceased. Aminoglutethimide is known to inhibit the formation of pregnenolone in the adrenal gland and block the aromatization of androgens to oestrogens in the peripheral tissue. Its administration leads to remission of 50% of oestrogen receptor positive tumours. In the last few years, several inhibitors of the steroid aromatase have been synthesized (2,7) and their clinical value will have to be examined. Since the successful introduction of tamoxifen, the method of antagonizing oestrogens at a cellular level has become important. The advantages of the anti-oestrogen treatment are somewhat diminished however by the fact that every third patient does not respond to this therapy despite the presence of oestrogen receptors at the tumour tissue. The reasons for these failures are still unknown. Defects in cellular regulation can be