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Biomedical subjects

B S Katzenellenbogen

Publications and source records attributed to B S Katzenellenbogen.

At least 181 records · Page 10Linked to original sources
PubMed1981

Tamoxifen aziridines: effective inactivators of the estrogen receptor.

Two analogs of the antiestrogen tamoxifen, which bear a chemically reactive aziridine function in place of the dimethylamino group, bind to the estrogen receptor from rat uterus and from MCF-7 human breast cancer cells and appear to react irreversibly with the receptor at the estrogen binding site, in a time-and concentration-dependent fashion. BEcause these compounds are effective receptor inactivators in uterus and breast cancer cells, they should prove to be useful probes for investigating the role of receptor in regulating cellular responses to estrogen and in studying the dynamics of estrogen receptor synthesis and turnover.

Animals↗
PubMed1979

Estrogen and antiestrogen action: studies in reproductive target tissues and tumors.

Studies are reported using unlabelled and radiolabelled antiestrogens which are aimed at elucidating the nature of interaction of antiestrogens with uterine and mammary tissue. Antiestrogens and long-acting estrogens move estrogen receptor sites to the nucleus and maintain elevated nuclear receptor levels for a prolonged period. The antagonistic action of antiestrogens in the uterus, however, appears to derive from their ability to effect a marked perturbation in the subcellular distribution of receptor whereby very little (ca. 10%) is cytoplasmic and further estrogen receptor accumulation is blocked. In DMBA-induced rat mammary tumors, the nonphototoxic antiestrogen, U-23, 469, effectively antagonizes the development and growth of tumors and elicits regression of 90% of established tumors with a time course similar to that seen after ovariectomy. Again, during antiestrogen treatment, the levels of cytoplasmic estrogen receptor are depressed with over 90% of total receptor being found in the nucleus. Two radiolabelled antiestrogens of high specific activity and purity have been prepared by us and their interaction with nuclear and cytoplasmic estrogen receptors is reported. Both 3H-CI-628 and 3H-U-23, 469 are metabolized in vivo to more polar forms which are found associated with the nuclear estrogen receptor, and which may be the true agents active in vivo.

Animals↗
PubMed1979

Androgen-uterine interactions: an assessment of androgen interaction with the testosterone- and estrogen-receptor systems and stimulation of uterine growth and progesterone-receptor synthesis.

This study investigates growth and the induction of progesterone-receptor synthesis in the immature (day 20--23) rat uterus after injection of different doses of 5 alpha-dihydrotestosterone (DHT) and testosterone (T) in long- and short acting injection vehicles. Moderate doses of T (300 microgram/day in saline for 3 days) elicit uterine growth (ca. 250% of control) that is abolished by concomitant injections of antiandrogen (1 mg flutamide/day or 8 mg DIMP/day) but is unaffected by injections of antiestrogens (60 microgram CI-628 or U11,100A/day). Uterine growth evoked by 17 beta-estradiol (3 microgram/day for 3 days) is, however, only antagonized with the antiestrogens but not antiandrogens. Experiments employing whole uteri in vitro indicate that the specific nuclear uptake of 10(-8) M [3H]T is markedly inhibited by the antiandrogens DIMP, flutamide, and the hydroxylated flutamide metabolite (LACT) [LACT greater than DIMP greater than FLUT] while the antiestrogens CI-628 and U11,100A are ineffective. In contrast, the specific nuclear uptake of 10(-8) M [3H]-estradiol is inhibited by only the antiestrogens and not antiandrogens. When very high (5 or 10 mg) doses of DHT Are administered in an oil-containing injection vehicle, nuclear translocation and cytoplasmic depletion of the estrogen receptor does occur and a uterotrophic response is elicited which is resistant to antagonism by antiandrogen. Likewise, the DHT-stimulated increase in progesterone-receptor content is not decreased by concomitant antiandrogen. Similar 5 or 10 mg doses of DHT, administered in a water-soluble dimethylsulfoxide vehicle, show little estrogen-receptor movement and the DHT-induced uterine growth and induction of progesterone-receptor synthesis is almost completely eliminated with antiandrogen. Regardless of the degree of uterine growth stimulation, however, the androgens are poor stimulators of uterine progesterone-receptor synthesis compared with estradiol. These results indicate that androgens may interact with both the androgen- and estrogen-receptor systems in the uterus in inducing uterine growth and that the nature of the cellular mechanism, i.e., whether the androgen- and/or estrogen-receptor system is involved, is dependent critically upon the in vivo dose of androgen and the mode of hormone administration.

Androgen Antagonists↗
PubMed1979

Antiestrogens and antiestrogen metabolites: preparation of tritium-labeled (+/-)-cis-3-[p-(1,2,3,4-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)phenoxyl]-1,2-propanediol (U-23469) and characterization and synthesis of a biologically important metabolite.

The Upjohn antiestrogen (+/-)-cis-3-[p-(1,2,3,4-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]-1,2-propanediol (2b, U 23469) has been prepared in tritium-labeled form by reduction of an unsaturated dihydronaphthalene precursor with carrier-free tritium gas over a palladium catalyst followed by alkylation with 3-iodo-1,2-propanediol. After extensive chromatographic purification, the final material was obtained with a specific activity of 13 Ci/mmol and a radiochemical purity of 94%. In vivo studies with immature rats show that [3H]2b is slowly converted to a more polar metabolite that is selectively accumulated in the nuclear fraction of the uterus where it is bound to the estrogen receptor. Chromatographic comparisons indicate that this metabolite is the demethylated analogue 2c, a compound that has an affinity for estrogen receptor more than 300 times greater than that of 2b. These studies suggest that the demethylated analogue 2c may be a biologically important metabolite of 2b that is involved in the action of this antiestrogen.

Animals↗
PubMed1979

Estrogenic activity of the insecticide chlordecone (Kepone) and interaction with uterine estrogen receptors.

The chlorinated insecticide chlordecone (Kepone) interacts with the estrogen receptor system in the rat uterus in vitro and in vivo. It competes with estradiol for binding to the cytoplasmic receptor in vitro and also induces nuclear accumulation of estrogen receptor sites in uteri in vitro. When injected into immature rats, chlordecone translocates estrogen receptor sites to the uterine nucleus, increases uterine weight, and stimulates the synthesis of the progesterone receptor, an estrogen receptor-mediated process. Its slow onset of action but prolonged duration of interaction with estrogen receptor and stimulation of uterine weight gain and progesterone receptor synthesis indicates that, although it has an affinity for receptor only 0.01-0.04% that of estradiol, its considerable estrogenic activity may likely be derived from its long half-life and bioaccumulative character.

Animals↗