This laboratory has identified an unusual non-polar, biosynthetic metabolite of estradiol, the lipoidal derivative, LE2, and showed it to be a heterogeneous family of fatty acid esters of estradiol, esterified specificity at C-17. These esters are biologically active and occur naturally in human blood. Studies are to be conducted to determine the physiological and pathophysiological role of LE2. The concentration of LE2 in serum of women will be measured to ascertain the effect of: menstrual cycle, menopause, pregnancy, obesity and cancer (endometrial, ovarian, breast). LE2 will also be assayed in human breast cyst fluid. The distribution of fatty acid esters of plasma LE2 will be determined and compared using radioimmunoassay in concert with high pressure liquid chromatography. Other experiments will ascertain whether these circulating compounds are estrogenic messengers that are specific for tissues containing esterases capable of releasing estradiol. A variety of C-17 esters of estradiol will be synthesized and their ability to bind to the estrogen receptor will be correlated with their structure as determined by x-ray crystallography. The biochemical mechanisms involved in the synthesis and hydrolysis of these unusual compounds will be investigated. Structural studies of a similar family of glucocorticoids will be initiated. This laboratory developed gamma-emitting estrogens capable of binding to the estrogen receptor with high affinity, the 16alpha halogenated analogs of estradiol. 16alpha-125I-Iodo-estradiol which we synthesized in carrier-free form (2200 Ci/mmol) is now used generally to measure estrogen receptor with great sensitivity. We have shown that this compound is specifically cytotoxic to estrogen sensitive cells. Further kinetic, in vitro studies are being performed to examine: the dose relationship of this cell killing; the possible role of DNA repair inhibitors in potentiating this effect; in vivo killing of estrogen sensitive cancers. The short range deoxynucliotide destruction caused by the 125I isotope will be used to identify the estrogen receptor DNA binding site. The uptake of the 125I-labelled estrogen and the correlation with tumor estrogen receptors is being measured in women undergoing surgery for ovarian or breast cancer. Analogs of 16alpha-125I estradiol which may be resistent to metabolism are being synthesized as possible superior probes for in vivo killing and imaging. 16alpha-123I-Estradiol will be used as a probe for the imaging of estrogen responsive tumors. Other classes of steroids labelled with 125I are to be synthesized as ligands for the androgen, progesterone and corticoid receptors.
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