Biochemical and biological aspects of anti-oestrogen action

Wakeling, A. E.; Slater, S. R.

doi:10.1007/978-1-349-81345-2_12

Cited by 8 publications

(6 citation statements)

References 46 publications

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“…However, it has been reported that iV-desmethyltamoxifen was more potent than 4-hydroxytamoxifen and TAM with respect to cytotoxicity for MCF-7 cells (8) and C3H/10T 1/2 cells (19). TAM and fcrans-4-hydroxytamoxifen were equipotent, which agrees with the results of Wakeling and Slater (10,35) and Kemps et al (11) in the rat uterus and disagrees with Jordan et al (31), who found 4-hydroxytamoxifen to be 8 times more potent than TAM. Metabolite Y and cis-4-hydroxytamoxifen were by far the least active drugs (26 and 27 times less potent than iV-desmethyltamoxifen respectively).…”

Section: Antiestrogenic Activitysupporting

confidence: 73%

Effects of Tamoxifen, Tamoxifen Metabolites, and Nafoxidine on Adenosine 3′,5′-Monophosphate Phosphodiesterase: Correlations with Growth Inhibitory Activities but not Estrogen Receptor Affinities^*

Fanidi

Courion-Guichardaz²,

Fayard³

et al. 1989

Endocrinology

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Triphenylethylenes [Tamoxifen (TAM), TAM metabolites, and nafoxidine] were found to inhibit Ca2+-calmodulin (CaM)-dependent cAMP phosphodiesterase (PDE) activity of the quail oviduct, whereas 17 beta-estradiol was inactive. The Ca2+-CaM-independent PDE activity was not affected by triphenylethylenes, suggesting that they do not interact directly with the active site of the enzyme. Kinetic analysis indicated that these drugs competitively inhibited the activation of PDE by CaM with the following potencies: N-desmethyltamoxifen, Ki = 3 microM; metabolite Z, trans-4-hydroxytamoxifen, and TAM Ki = 5 microM; nafoxidine, Ki = 8.5 microM; and metabolite Y and cis-4-hydroxytamoxifen, Ki = 50 microM. Injected alone into immature quails, none of these drugs significantly affected oviduct weight. When administrated together with estradiol benzoate, these drugs reduced the trophic effect of estradiol in a dose-dependent relationship, with ID50 values ranging from 0.07 mg/kg for N-desmethyltamoxifen to 2.02 mg/kg for cis-4-hydroxytamoxifen. The order of growth inhibitory potency was not correlated with estrogen receptor affinities, but was the same as that reported for PDE inhibition. This correlation suggests that interaction of antiestrogen with Ca2+-CaM dependent PDE may be one of the mechanisms responsible for the estrogen antagonist activity of these drugs.

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Section: Antiestrogenic Activitysupporting

confidence: 73%

Effects of Tamoxifen, Tamoxifen Metabolites, and Nafoxidine on Adenosine 3′,5′-Monophosphate Phosphodiesterase: Correlations with Growth Inhibitory Activities but not Estrogen Receptor Affinities^*

Fanidi

Courion-Guichardaz²,

Fayard³

et al. 1989

Endocrinology

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“…The number of animal replicates is shown in parentheses. However, tamoxifen has other reported effects, including oestradiolic activity (Wakeling & Slater, 1981;Wakeling & Bowler, 1987;Yang et al, 1996) and suppression of systemic androgen levels (Bartke et al, 1978;Lacroix et al, 1987), which do not preclude other interpretations of the data. a p < 0.05, b p < 0.01 and c p < 0.001 indicate signi®cant differences between means for untreated and treated rats within each column.…”

Section: Discussionmentioning

confidence: 98%

Perturbation of fluid reabsorption in the efferent ducts of the rat by testosterone propionate, 17β‐oestradiol 3‐benzoate, flutamide and tamoxifen

1997

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The regulation by oestradiol and testosterone of fluid reabsorption in the efferent ducts of the rat was investigated by determining the effects of administering the hormones and their antagonists. Untreated rats were compared to animals treated for 7 days with testosterone propionate (1 mg d(-1)), oestradiol benzoate (400 microg d(-1)), flutamide (10 mg d(-1)) or tamoxifen (1 mg d(-1)). Two procedures were used to measure perturbation of transepithelial fluid fluxes in vivo. The first procedure used cannulation of the proximal epididymal duct and micropuncture of the rete testis to compare the rate at which fluid enters and leaves the efferent ducts. Oestradiol administration increased (p < 0.001) the volume of fluid entering the epididymal duct from the efferent ducts (i.e. reduced reabsorption) while flutamide and tamoxifen decreased (p < 0.05) the amount of fluid entering the epididymal duct (i.e. increased fluid reabsorption). Testosterone did not have a statistically significant effect, although it produced a small increase in fluid reabsorption. There was some perturbation of the concentration of electrolytes and the osmotic pressure of the fluid leaving the efferent ducts, but as these were not large, it is suggested that the treatments had little effect on the basic mechanisms of osmotic water transport via solute-solvent coupling. The second procedure used to test the effect of the steroids involved microperfusing individual efferent ducts, and the results were consistent with those of the first study. Oestradiol decreased fluid reabsorption by the efferent ducts (p < 0.05), and testosterone (p < 0.05, lowest perfusion rate only), flutamide (p < 0.001) and tamoxifen (p < 0.01) increased reabsorption. The similar responses to flutamide and testosterone administration suggest that flutamide acted as an androgenic agonist by elevating systemic and luminal androgen. It is concluded that fluid reabsorption in the efferent ducts is perturbed by oestrogens and androgens. Although their actions have not been completely resolved, it is proposed that they are involved in a chronic regulation, with androgens stimulating and oestrogens suppressing fluid reabsorption by the ducts.

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“…Nevertheless, the metabolically activated antiestrogen, e.g. trans-4-monohydroxytamoxifen (OH-TAM), has about equal agonistic activity in various tests to that found with tamoxifen [11]. Even the potent benzothiophene derivatives LYl17018 [12] and keoxifene (LY 156758) [13] display significant uterotrophic activity in the rat, although they have somewhat higher relative antiuterotrophic activity than triphenylethylene derivatives [12,13].…”

Section: Introductionmentioning

confidence: 97%

Antiestrogenic properties of keoxifene,trans-4-hydroxytamoxifen, and ICI 164384, a new steroidal antiestrogen, in ZR-75-1 human breast cancer cells

Poulin

Mérand

Poirier

et al. 1989

Breast Cancer Res Tr

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The agonistic/antagonistic properties of two non-steroidal antiestrogens, namely trans-4-monohydroxytamoxifen (OH-TAM) and keoxifene (LY156758), and the new steroidal antiestrogen ICI164384, a 7 alpha-alkylamide derivative of estradiol (E2), were assessed by measuring their effect on the proliferation of ZR-75-1 cells, an estrogen-responsive human breast cancer cell line. While subnanomolar concentrations of both OH-TAM and LY156758 had significant estrogenic stimulatory activity on cell growth in the absence of estrogens and higher concentrations were inhibitory, ICI164384 behaved exclusively as a growth inhibitor and more potently so than the two other compounds. The three antiestrogens had similar potency to inhibit the mitogenic effect of E2 and at 300 nM, all antiproliferative effects were completely reversible by the estrogen. ICI164384 was a weaker competitor of 3H-labeled E2 or R2858 (moxestrol) uptake in intact ZR-75-1 cells in a 1-hour assay, partly because of a slower intracellular access to estrogen specific binding sites. Moreover, ICI164384 interacted in a rapidly (approximately 6 h) reversible manner with estrogen-specific binding sites, while the non-steroidal antiestrogens induced a longer-acting (greater than 24 h) down-regulation of specific [3H]R2858 uptake. The present data indicate that, among the antiestrogens studied, ICI164384 is the only compound acting as a pure antiestrogen in ZR-75-1 breast cancer cells, while LY156758 and OH-TAM behave as antiestrogens endowed with partial agonistic activity in this system.

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Biochemical and biological aspects of anti-oestrogen action

Cited by 8 publications

References 46 publications

Effects of Tamoxifen, Tamoxifen Metabolites, and Nafoxidine on Adenosine 3′,5′-Monophosphate Phosphodiesterase: Correlations with Growth Inhibitory Activities but not Estrogen Receptor Affinities^*

Effects of Tamoxifen, Tamoxifen Metabolites, and Nafoxidine on Adenosine 3′,5′-Monophosphate Phosphodiesterase: Correlations with Growth Inhibitory Activities but not Estrogen Receptor Affinities^*

Perturbation of fluid reabsorption in the efferent ducts of the rat by testosterone propionate, 17β‐oestradiol 3‐benzoate, flutamide and tamoxifen

Antiestrogenic properties of keoxifene,trans-4-hydroxytamoxifen, and ICI 164384, a new steroidal antiestrogen, in ZR-75-1 human breast cancer cells

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Biochemical and biological aspects of anti-oestrogen action

Cited by 8 publications

References 46 publications

Effects of Tamoxifen, Tamoxifen Metabolites, and Nafoxidine on Adenosine 3′,5′-Monophosphate Phosphodiesterase: Correlations with Growth Inhibitory Activities but not Estrogen Receptor Affinities*

Effects of Tamoxifen, Tamoxifen Metabolites, and Nafoxidine on Adenosine 3′,5′-Monophosphate Phosphodiesterase: Correlations with Growth Inhibitory Activities but not Estrogen Receptor Affinities*

Perturbation of fluid reabsorption in the efferent ducts of the rat by testosterone propionate, 17β‐oestradiol 3‐benzoate, flutamide and tamoxifen

Antiestrogenic properties of keoxifene,trans-4-hydroxytamoxifen, and ICI 164384, a new steroidal antiestrogen, in ZR-75-1 human breast cancer cells

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Effects of Tamoxifen, Tamoxifen Metabolites, and Nafoxidine on Adenosine 3′,5′-Monophosphate Phosphodiesterase: Correlations with Growth Inhibitory Activities but not Estrogen Receptor Affinities^*

Effects of Tamoxifen, Tamoxifen Metabolites, and Nafoxidine on Adenosine 3′,5′-Monophosphate Phosphodiesterase: Correlations with Growth Inhibitory Activities but not Estrogen Receptor Affinities^*