An isotopic infusion technique has been used in an attempt to determine the contribution that local, in situ, oestrone synthesis makes to the oestrogen content of breast tumours. 3H-Androstenedione and 14C-oestrone were infused into women with advanced breast cancer for 12 hr before operation. At surgery, normal breast and breast tumour biopsy samples were obtained and 3H-androstenedione, 3H-oestrone derived from 3H-androstenedione and 14C-oestrone were isolated and measured. DNA polymerase alpha activity, a marker of cellular proliferation, was also measured to examine whether local synthesis of oestrone exerted a biological effect. The study was repeated after patients had been treated with the aromatase inhibitor, 4-hydroxyandrostenedione, before undergoing further surgery for removal of their tumours. In 4/6 tumours examined, in situ synthesis of 3H-oestrone from 3H-androstenedione accounted for the major part (84.3 +/- 9.0%) of the 3H-oestrone detected, while no significant in situ synthesis occurred in 2 other tumours. Although treatment with 4-hydroxyandrostenedione did not significantly alter the uptake of 3H-androstenedione or 14C-oestrone into breast tissues, in situ formation of 3H-oestrone was only detected in one tumour sample after treatment. DNA polymerase alpha activity decreased in 4/6 tumours after treatment with 4-hydroxyandrostenedione. Overall, however, there was no significant correlation between the level of 3H-oestrone formed in situ and DNA polymerase alpha activity (r = 0.38, NS). It is concluded that in some, but not all, breast tumours in situ formation of oestrone can make an important contribution to the oestrogen content of breast tumours.
Human breast cancer cells (MCF-7) showed increased responses to methotrexate and vincristine after a 48-hr pretreatment with medroxyprogesterone acetate. The effect of the hormone, which was detectable at concentrations of between 10 and IOOnM, was independent of its growth-inhibitory action. These findings confirm a previous clinical study and have important implications with regard to the management of advanced breast cancer.
SynopsisUptake of oestrogens into breast tissue and their subsequent metabolism can be studied by infusing radio-labelled steroids into volunteer patients. Such studies show that oestradiol is preferentially accumulated in breast tumours, oestradiol concentrations exceeding those of oestrone. This contrasts with plasma, in which oestrone concentrations in postmenopausal women are greater than those of the oestradiol. This observation suggests that tissue factors can modulate local oestrogen metabolism, and thus local steroid concentrations.We have studied the local production of oestrogens from androgen, and also the interconversion of the major oestrogens, oestrone and oestradiol. Using isotopic techniques, it is possible to calculate the proportion of endogenous oestrogen produced from androgen, as opposed to uptake from the circulation. These studies suggest that a very variable proportion of tissue oestrogen derives from endogenous synthesis. After administration of aromatase inhibitors, aromatase activity is substantially inhibited, both in vivo and in vitro.Relative oestrogen concentrations are determined in part by the activity of oestradiol dehydrogenase. In breast tissue, dehydrogenase activity is present and this is modified by various factors, including androgens. In addition, we have demonstrated that normal, benign and malignant breast tissues produce factors which can modulate both growth and dehydrogenase activity of cancer cells in vitro.We conclude that breast tissue is a site of synthesis of oestrogens, and that a number of factors can affect their local concentration. Tumour cells produce growth factors which can influence steroid metabolism, and may thus be able to enhance favourably their own endocrine environment.
Exposure of cultured human breast cancer cells (MCF-7) to medroxyprogesterone acetate (MPA) prior to treatment with adriamycin (ADR) enhanced the effect of the cytotoxic drug on cell yield after further growth of viable cells. Pretreatment with oestradiol (E2) produced similar synergism, but no such effect was observed using dexamethasone. Exposure to ADR before MPA led to an additive effect, but not to synergism. When cells resistant to the growth-inhibitory action of MPA were examined, progestogen/drug synergism could still be demonstrated. We conclude that the effects of ADR, like those of methotrexate and vincristine, can be enhanced by pre-treatment with MPA and that further clinical trials of such a regimen are needed.
judgmental approach to such patients to be more readily achieved. From the theoretical point of view, much of the nosological debate incorporating inferred degrees of suicidal intent is rendered unnecessary, as the differences are more apparent than real, with the primary activity being that of conservation withdrawal in order to escape an intolerable situation.
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