Search Results
You are looking at 1 - 10 of 12 items for
- Author: V. C. JORDAN x
- Refine by access: All content x
Search for other papers by C. J. DIX in
Google Scholar
PubMed
Search for other papers by V. C. JORDAN in
Google Scholar
PubMed
The administration of either monohydroxytamoxifen (25 μg) or oestradiol benzoate (25 μg) to immature rats resulted in similar depletion of the cytoplasmic oestrogen-receptor pool, with a transient (approx. 48 h) increase in nuclear oestrogen-receptor levels. Oestradiol benzoate increased uterine wet weight with a corresponding increase in uterine cytoplasmic progesterone-receptor levels, DNA content and cell division at 48 h. In contrast, monohydroxytamoxifen produced only a partial increase in uterine wet weight. Although the increase in concentration of uterine progesterone receptors (per mg DNA) by monohydroxytamoxifen was comparable to that produced by oestradiol benzoate, the nuclear antioestrogen–oestrogen-receptor complexes were unable to stimulate a large rise in whole uterine DNA content and cell division. Examination of stromal and epithelial mitotic activity 48 h after administration of 0·25, 2·5 and 25 μg oestradiol benzoate, monohydroxytamoxifen or tamoxifen showed that the inability of antioestrogens to stimulate oestrogenlike mitotic activity was not related to the dose of antioestrogen that was administered. It is suggested that the inability of the antioestrogen–oestrogen-receptor complexes to initiate the nuclear events which lead to cell division should be exploited in the investigation of the nuclear mechanism of oestrogen action. The high potency of monohydroxytamoxifen and its inherent biological activity, in that it is not metabolically activated before exerting its effects, provide clear advantages for its future use as a pharmacological probe.
Search for other papers by V. C. JORDAN in
Google Scholar
PubMed
Search for other papers by LYNNE J. DOWSE in
Google Scholar
PubMed
SUMMARY
Tamoxifen (ICI 46,474) has been shown to possess anti-tumour properties in the dimethylbenz(a)anthracene (DMBA)-induced rat mammary carcinoma model. During tamoxifen therapy the binding of [3H]oestradiol in vivo to uterine (P < 0·001), vaginal (P < 0·01) and tumour (P < 0·001) tissues was significantly reduced. Tamoxifen therapy was without effect on the binding of [3H]oestradiol in heart tissue. The determination of specific oestrogen-binding components in vitro was significantly reduced (P < 0·01) in tumours from tamoxifen-treated rats and tamoxifen inhibited the binding of [3H]oestradiol to 8S oestrogen-binding components, derived from rat uteri and DMBA-induced tumours, in vitro.
Search for other papers by V. C. JORDAN in
Google Scholar
PubMed
Search for other papers by S. KOERNER in
Google Scholar
PubMed
SUMMARY
Four-day cyclic rats fed 7,12-dimethylbenz(a)anthracene (DMBA) (20 mg) at 50 days of age had peak prolactin, oestradiol and uterine wet weights at pro-oestrus. Tamoxifen (50, 200 and 800 μg daily), administered to ovariectomized rats, produced significant (P < 0·05) decreases in oestrogen-stimulated prolactin levels but was unable to reduce prolactin to control values. Tamoxifen (12·5, 50 and 200 μg daily) produced decreases in size in DMBAinduced rat mammary carcinomata in intact rats although some tumours did not respond to therapy. The ability of the pituitary to produce prolactin was not impaired. Decreases in uterine wet weights and peripheral oestradiol levels occurred during tamoxifen treatment.
Search for other papers by V. C. JORDAN in
Google Scholar
PubMed
Search for other papers by T. JASPAN in
Google Scholar
PubMed
SUMMARY
Rats with growing 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary carcinomata were biopsied and oestrogen-binding capacity was measured using a Sephadex LH-20 chromatography method. Tumours were measured with calipers and animals were treated for 3 weeks with tamoxifen (50 μg/day, s.c.). Tumour response was determined by the size (cm2) before and after therapy. An increase in tumour regression (ten tumours) was seen with increasing oestrogen-binding sites determined by Scatchard analysis (P < 0·01). Thirty tumours were used to determine oestrogen binding with a single dose of [3H]-oestradiol. The percentage tumour regression was linearly correlated with oestrogen-binding capacity (P < 0·01), although some tumours with high oestrogen-binding capacities only partially regressed in response to tamoxifen therapy. The time of the oestrous cycle when biopsy occurred was not a critical factor in determining oestrogen binding for prediction of response. Oestrogen binding was reduced during tamoxifen therapy.
Search for other papers by V. C. JORDAN in
Google Scholar
PubMed
Search for other papers by G. PRESTWICH in
Google Scholar
PubMed
Department of Pharmacology, School of Medicine, Leeds, LS2 9NL
(Received 10 August 1977)
Oestradiol produces hyperplasia of the rat uterine endometrium whereas anti-oestrogens produce hypertrophy (Kang, Anderson & DeSombre, 1975). At the subcellular level, oestradiol stimulates an increase in the concentration of progesterone receptors (Milgrom & Baulieu, 1970) and we have now compared the response to oestradiol with that to two non-steroidal anti-oestrogens, tamoxifen (trans-1-(4-β-dimethylaminoethoxyphenyl)-1, 2-diphenyl-but-1-ene) and monohydroxytamoxifen (1-(4-β-dimethylaminoethoxyphenyl)-1-(4-hydroxyphenyl)-2-phenyl-but-1-ene; Jordan, Collins, Rowsby & Prestwich, 1977).
Mature female rats (130–150 g, Alderley Park strain) were ovariectomized under ether anaesthesia and used for experiments 4 days later. Oestradiol-17β (5 μg), tamoxifen (50 μg) and monohydroxytamoxifen (50 μg) were injected s.c. in 0·1 ml arachis oil and the animals were killed after 6, 24, 48 or 72 h. Controls received arachis oil alone. Uteri were dissected out and weighed wet on a torsion balance. Tissues were homogenized (4 °C) in 2 ml Tris
Search for other papers by R. E. HUNTER in
Google Scholar
PubMed
Search for other papers by V. C. JORDAN in
Google Scholar
PubMed
Department of Obstetrics & Gynecology, The Memorial Hospital, Worcester, Massachusetts, and *Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545, U.S.A.
(Received 14 January 1975)
Evans & Hähnel (1971) and Trams, Engel, Lehmann & Maass (1973) have reported that during the endometrial proliferative stage of the human menstrual cycle oestrogen-binding capacity is high, but during the secretory stage of the cycle, when progesterone is the dominant ovarian hormone, oestrogen-binding capacity is reduced. Sucrose density gradient analysis of human uterine cytosol has demonstrated oestradiol-17β-binding components sedimenting at 5 S (Wyss, Heinrichs & Herrmann, 1968) or 4 S and 8 S (Martin, 1972) although in neither study was the cycle time of the tissue reported.
Evans & Hähnel (1971) found that bound oestradiol-17β was located in the endometrium and the present study was undertaken to determine the presence or absence of the 8 S oestrogen-binding component in human endometrium during the menstrual cycle.
Search for other papers by V. C. JORDAN in
Google Scholar
PubMed
Search for other papers by S. KOERNER in
Google Scholar
PubMed
Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545, U.S.A.
(Received 28 August 1974)
Harper & Walpole (1967 reported the potent antioestrogenic activity of ICI 46,474, the trans-isomer of 1-(p-β-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene, in the rat; however, in the mouse the compound exhibited only oestrogenic properties. However, Emmens (1971) showed that large doses of ICI 46,474 or the related compound H774 (1-(p-β-diethylaminoethoxyphenyl)-1,2-di(p-methoxyphenyl)-but-1-ene citrate) caused vaginal refractoriness to oestradiol for several weeks after s.c. administration to ovariectomized mice. The present study was undertaken to determine the ability of ICI 46,474 and H774 to inhibit binding of [3H]oestradiol to the 8 S oestrogen receptor derived from ovariectomized mouse uterus and vagina.
Mature, Charges River CD strain mice were ovariectomized under ether anaesthesia, primed with 1 μg oestradiol-17β in 0·05 ml peanut oil and used for experimentation 2 weeks later. Animals were killed by cervical dislocation and the uteri and vaginae were dissected out, weighed and immediately
Search for other papers by V. C. JORDAN in
Google Scholar
PubMed
Search for other papers by S. KOERNER in
Google Scholar
PubMed
Search for other papers by C. ROBISON in
Google Scholar
PubMed
Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545, U.S.A.
(Received 8 November 1974)
Oestrogens have been found to stimulate prolactin release in the rat (Chen & Meites, 1970) and increases in prolactin in the circulation have been reported to be essential for the maintenance and growth of dimethylbenz(α)anthracene (DMBA)-induced rat mammary carcinomata (Pearson, Molina, Butler, Llerena & Nasr, 1972). Non-steroidal anti-oestrogens retard the growth of DMBA-induced rat mammary carcinoma (Schulz, Haselmayer & Hölzel, 1971; Terenius, 1971) and one such compound nafoxidine (U-11, 100A) has been shown to inhibit oestrogen-stimulated prolactin release in rats (Heuson, Waelbroeck, Legros, Gallez, Robyn & L'Hermite, 1971–72) thereby suggesting a mechanism for antitumour activity which may occur simultaneously with tumour oestrogen receptor blockade (Terenius, 1971). The present investigation was undertaken to determine whether other anti-oestrogens could control oestrogen-stimulated prolactin release.
The non-steroidal anti-oestrogens ICI 46,474 (tamoxifen, trade name Nolvadex, trans 1-(ρ-β-dimethylaminoethoxyphenyl)-1,2-diphenyl but-1-ene) and MER 25 (ethamoxytriphetol,
Search for other papers by V. C. JORDAN in
Google Scholar
PubMed
Search for other papers by LINDA ROWSBY in
Google Scholar
PubMed
Search for other papers by C. J. DIX in
Google Scholar
PubMed
Search for other papers by G. PRESTWICH in
Google Scholar
PubMed
The dose-related effects of non-steroidal antioestrogens and oestrogens on the measurement of cytoplasmic oestrogen receptors in the rat uterus have been determined. The simultaneous administration of tamoxifen or monohydroxytamoxifen and oestradiol on three consecutive days resulted in dose-dependent decreases in both the wet weight of the uterus and the number of available cytoplasmic oestrogen receptors. The oestrogenic triphenylethylenes ICI 47 699 and ICI 3188 both produced dose-dependent decreases in the number of available cytoplasmic oestrogen receptors. Increasing doses of ICI 47 699 resulted in increasing concentrations of oestrogen receptors within the nucleus. The effects of tamoxifen and oestradiol-17β were compared in the ovariectomized mouse; replenishment of uterine oestrogen receptors was less evident in tamoxifen-treated animals than in animals receiving oestradiol, although increases in uterine weight were similar. A single large dose of tamoxifen (50 μg) produced a prolonged depletion of cytoplasmic oestrogen receptors whilst stimulating rises in uterine weight and DNA and protein content. The results demonstrate that the depletion of the uterine cytoplasmic oestrogen receptor pool is a function of the dose administered for any compound with the ability to translocate oestrogen receptors to the nucleus and as such is not an exclusive characteristic of non-steroidal antioestrogens.
Search for other papers by A. C. ABBOTT in
Google Scholar
PubMed
Search for other papers by E. R. CLARK in
Google Scholar
PubMed
Search for other papers by V. C. JORDAN in
Google Scholar
PubMed
Department of Pharmacology, School of Medicine, Leeds, LS2 9NL
(Received 8 December 1975)
The introduction of two methyl groups positioned ortho to the side-chain in aryl alkyl ethers is known to alter the pharmacological properties and to limit the possible conformations of the side-chain (Clark & Williams, 1967; Clark, Dawes & Williams, 1968; Coggan, McPhail & Roe, 1969). The anti-oestrogens tamoxifen, clomiphene and nafoxidine all possess β-aminoethoxy side-chains and Lednicer, Lyster & Duncan (1967) demonstrated the importance of side-chain length and its position in space for biological activity.
Tamoxifen [trans-1-(4-β-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene], a potent anti-oestrogen in the rat, exhibits oestrogenic activity in the mouse and slight oestrogenic activity may also be demonstrated in the rat at high dose levels (Harper & Walpole, 1966). Furthermore, tamoxifen has been shown to be capable of inhibiting oestradiol binding in the mouse uterus both in vitro (Terenius, 1971; Skidmore, Walpole & Woodburn, 1972; Jordan & Koerner,
