Prolonged Antioestrogenic Activity of Ici 46,474 in the Ovariectomized Mouse

Vc, Jordan

doi:10.1530/jrf.0.0420251

Cited by 47 publications

(8 citation statements)

References 10 publications

(14 reference statements)

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“…The enduring suppres sive effects of Tamoxifen on mammary carcinogenesis may be due, at least in part, to the slow release of the anticstrogen from the vehicle (peanut oil). Prolonged antiestrogen effects of Tamoxifen, when administered in peanut oil, have previously been reported in labora tory animals [7). Although a definitive synergism be tween Tamoxifen and CB-154 was observed when the 'antihormones' were administered at the time of car cinogen treatment, this was not observed when the combined treatment was initiated beginning 33 days after carcinogen treatment.…”

Section: Discussionmentioning

confidence: 85%

“…The most prominent of these drugs are the antiestrogens and the prolactin-suppressing ergot alkaloids and ergoline derivatives. To date, the most widely used antiestrogen, experimentally and clinically, is Tamoxifen (1CI 46, 474) [7,8,11,12] a potent estrogen antagonist which acts by competing for cytoplasmic receptor com plex, by altering the association of the receptor complex and nuclear binding sites and/or by interfering with the regeneration of the cytoplasmic receptor [9], The most commonly used prolactin suppressor is 2-bromo-aergocryptine (CB-154) [1,3,5,6, 17] a dopaminergicagonist, which inhibits prolactin secretion in lower ani mals and in humans by acting at the level of the hypo thalamus and/or directly on the anterior pituitary gland [4], Clinically, these drugs have received considerable attention for they appear to have the potential of elim inating the need for certain endocrine ablative proce dures.…”

Section: Introductionmentioning

confidence: 99%

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2-Bromo-<i>α</i>-Ergocryptine (CB-154) and Tamoxifen (ICI 46,474) Induced Suppression of the Genesis of Mammary Carcinomas in Female Rats Treated with 7,12-Dimethylbenzanthracene (DMBA): A Comparison

Welsch¹,

Goodrich-Smith²,

Brown³

et al. 1982

Oncology

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Daily treatment of female Sprague-Dawley rats with CB-154 (prolactin suppressor) or Tamoxifen (estrogen antagonist) for 33 days before and after 7,12-dimethylbenzanthracene (DMBA) administration reduced (p < 0.05) the incidence of mammary carcinomas by 58 and 49%, respectively. A combination of CB-154 and Tamoxifen further reduced (p < 0.05) mammary carcinoma incidence by an additional 50–59%. Treatment with Tamoxifen for 66 days beginning 33 days after carcinogen treatment reduced (p < 0.05) the incidence of mammary carcinomas by 65%; CB-154 treatment, during the same time period, did not significantly effect the final yield of mammary carcinomas. The combination of Tamoxifen and CB-154 was comparable to Tamoxifen alone in suppressing the incidence of mammary carcinomas in the latter study. These results demonstrate a substantial suppressive and synergistic effect of Tamoxifen and CB-154 in the initiating phases of mammary carcinogenesis while in the early promoting phases of this oncogenic process, short-term treatment with Tamoxifen was superior to CB-154 treatment; no synergism between these clinically important compounds was observed.

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Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

2-Bromo-<i>α</i>-Ergocryptine (CB-154) and Tamoxifen (ICI 46,474) Induced Suppression of the Genesis of Mammary Carcinomas in Female Rats Treated with 7,12-Dimethylbenzanthracene (DMBA): A Comparison

Welsch¹,

Goodrich-Smith²,

Brown³

et al. 1982

Oncology

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“…Both these compounds are chemical derivatives of the highly potent synthetic nonsteroidal estrogen diethylstilbestrol (Furr and Jordan, 1984). Early studies revealed that tamoxifen could compete with estrogens, in terms of preventing 3 H]estradiol in ER target tissues (e.g., uterine, vaginal, and mammary) of mice, rats, and humans (Emmens, 1971;Lunan and Green, 1974;Jordan, 1975;Jordan and Dowse, 1976). These studies also provided insight into the pharmacokinetic/ pharmacodynamic properties of tamoxifen, including its conversion into the metabolite 4-hydroxytamoxifen (Fig.…”

Section: Selective Estrogen Receptor Modulatorsmentioning

confidence: 99%

Nuclear Receptors and Their Selective Pharmacologic Modulators

et al. 2013

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“…However, high doses of tamoxifen administered subcutaneously can cause the vagina to become refractory and unable to respond to administered estradiol (27,28). Similarly, prolonged administration of tamoxifen to mice causes the uterus to respond as if the drug was a partial agonist with potential antiestrogenic properties (29).…”

Section: Pharmacology Of Tamoxifenmentioning

confidence: 99%

Metabolites of tamoxifen in animals and man: Identification, pharmacology, and significance

Jordan

Chem

1982

Breast Cancer Res Tr

128

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Over the past decade, the non-steroidal antiestrogen tamoxifen has gained general acceptance for the palliative treatment of breast cancer. Although there has been much interest in the pharmacology of tamoxifen, our knowledge of its metabolism in laboratory animals and patients is incomplete and the precise mechanism of action within target tissue and breast tumor cells is unknown. This review briefly describes the pharmacology of tamoxifen in various laboratory species and patients. Several metabolites of tamoxifen are known and their relative potencies as estrogens and antiestrogens are compared with the parent compound. Apart from monohydroxytamoxifen, none of tamoxifen's metabolites are more potent antiestrogens, but a metabolite in the dog, Metabolite E, is fully estrogenic. Routine assays (tlc, HPLC, glc/ms) are available to detect tamoxifen, N-desmethyltamoxifen, monohydroxytamoxifen, and a newly identified metabolite, designated Metabolite Y, in biological fluids. Continuous therapy with tamoxifen (10 mg bid) produces steady-state levels (100-200 ng/ml serum) within 4 weeks. Levels of N-desmethyltamoxifen are often up to twice the levels achieved with tamoxifen, while levels of monohydroxytamoxifen and Metabolite Y are below 10 ng/ml. Although monohydroxytamoxifen has a high binding affinity for the estrogen receptor, the metabolic activation of tamoxifen is an advantage rather than a requirement for antiestrogenic activity. The action of tamoxifen in vivo is the net result of the individual actions of the parent compound and its metabolites competing for the occupation of receptors within target tissues and tumors.

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Prolonged Antioestrogenic Activity of Ici 46,474 in the Ovariectomized Mouse

Cited by 47 publications

References 10 publications

2-Bromo-<i>α</i>-Ergocryptine (CB-154) and Tamoxifen (ICI 46,474) Induced Suppression of the Genesis of Mammary Carcinomas in Female Rats Treated with 7,12-Dimethylbenzanthracene (DMBA): A Comparison

2-Bromo-<i>α</i>-Ergocryptine (CB-154) and Tamoxifen (ICI 46,474) Induced Suppression of the Genesis of Mammary Carcinomas in Female Rats Treated with 7,12-Dimethylbenzanthracene (DMBA): A Comparison

Nuclear Receptors and Their Selective Pharmacologic Modulators

Metabolites of tamoxifen in animals and man: Identification, pharmacology, and significance

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