AROMATASE INHIBITORS, BREAST CANCER, AND OTHER DISEASES

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In previous studies 4-hydroxyandrostenedione (4-OHA) was found to be a potent inhibitor of estrogen biosynthesis. The compound reduces estrogen secretion and caused regression of DMBA-induced mammary tumors in rats. It is now proposed to evaluate 4-OHA in postmenopausal breast cancer patients and also in patients with other diseases in which estrogen plays a role. Recent findings that 4-OHA and other steroidal aromatase inhibitors cause inactivation of the enzyme will be investigated by kinetic and radiolabeling techniques. Radiolabeled aromatase inhibitor would be used to determine the half-life and number of binding sites of aromatase. Studies are described to investigate the differential effect of 4-OHA on the uterus and DMBA-induced mammary tumors of the rat. Tissue weight, cytosolic and nuclear estrogen receptors and progesterone receptors will be quantitated. Serum estradiol levels have been reported to be increased in men with myocardial infarction and angina. Aromatase inhibitor treatment might be of value in patients at risk for myocardial infarction if estradiol is important in this disease. To determine whether increased estradiol in patients is due to increased production or reduced clearance of estradiol, peripheral aromatization and metabolic clearance rate of estradiol would be measured as well as plasma concentrations in patients. If the increase in blood level is due to increased production, studies would be undertaken to investigate whether estradiol has any etiological role in the disease by determining concentrations of estrogen receptors in human heart and vascular tissue and the effect of estradiol on isolated coronary artery smooth muscle. Various factors affecting aromatization in peripheral tissue will also be investigated in vitro.