An evaluation of tamoxifen as a partial agonist by classical receptor theory — An explanation of the dual action of tamoxifen

Macnab, Malcolm W.; Tallarida, Ronald J.; Joseph, Rosaline R.

doi:10.1016/0014-2999(84)90493-x

Cited by 41 publications

(12 citation statements)

References 11 publications

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“…30 Although our data clearly show similar effects of chronic treatment with tamoxifen and E 2 , it is unknown whether tamoxifen antagonizes the vascular action of E 2 in estrogen-deficient animal models. Our results demonstrate that chronic tamoxifen does not inhibit effects of E 2 treatment on cerebrovascular contractions.…”

Section: Discussionmentioning

confidence: 65%

Estrogen and Tamoxifen Modulate Cerebrovascular Tone in Ovariectomized Female Rats

et al. 2004

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Abstract-Postmenopausal estrogen deficiency increases the incidence of cerebrovascular disease. However, hormone replacement therapy is associated with an increased cardiovascular risk. Tamoxifen is a selective estrogen receptor modulator with estrogenic effects on cardiovascular risk factors, but its long-term impacts on cerebral vasculature are unknown. We hypothesized that chronic 17␤-estradiol or tamoxifen treatment exerted similar effects in reducing cerebrovascular tension in ovariectomized rats. We therefore determine whether (1) chronic 17␤-estradiol treatment could influence vasomotor activities, (2) chronic tamoxifen therapy could exert an estrogen-like or estrogen-antagonistic effect, and (3) acute exposure to estrogen could mimic the effect of 17␤-estradiol. Isometric tension was measured in cerebral arteries from female rat groups: control, ovariectomy, ovariectomy plus 17␤-estradiol treatment, ovariectomy plus tamoxifen treatment, and ovariectomized rats treated with tamoxifen and 17␤-estradiol. Ovariectomy enhanced cerebrovascular contractions to endothelin-1 or CaCl 2 , but not to U46619 or phenylephrine. 17␤-Estradiol therapy reversed these effects. Chronic tamoxifen treatment exerted estrogen-like actions by reversing ovariectomy-induced enhancement of vessel tone without antagonizing the effect of chronic 17␤-estradiol treatment. Ovariectomy enhanced the relaxing potency of nicardipine, and 17␤-estradiol treatment prevented this effect. Acute exposure to 10 Ϫ9 mol/L 17␤-estradiol or 10 Ϫ8 mol/L tamoxifen did not modulate contractions in rings from nonoperated female rats. In conclusion, ovariectomy differentially enhances agonist-induced cerebrovascular tone, an effect that was reversed by estrogen therapy. Tamoxifen does not act as an estrogen antagonist; instead, it functions as an estrogen agonist during estrogen deficiency. Thus, tamoxifen may confer beneficial effects similar to estrogen in cerebrovascular vessels.

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Section: Discussionmentioning

confidence: 65%

Estrogen and Tamoxifen Modulate Cerebrovascular Tone in Ovariectomized Female Rats

et al. 2004

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“…Tamoxifen is known to have varied biological effects ranging from complete estrogen antagonism to pure estrogen agonism depending upon its concentration, the sex of the animal, and the target organ (Furr and Jordan 1984;MacNab et al 1984;Wade and Powers 1993). In humans and rats, tamoxifen is predominantly antiestrogenic with residual estrogenic activities (Furr and Jordan 1984).…”

Section: Discussionmentioning

confidence: 99%

Tamoxifen: 28-day oral toxicity study in the rat based on the Enhanced OECD Test Guideline 407 to detect endocrine effects

Kennel

Pallen

Barale-Thomas

et al. 2003

Archives of Toxicology

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The main objective of this 28-day oral gavage toxicity study in the rat was to investigate which of the current and/or additional parameters of the OECD Test Guideline 407 would reliably and sensitively detect the endocrine-mediated effects of the nonsteroidal antiestrogen tamoxifen. In addition, as this study was performed using two subgroups of five animals of each sex run concurrently, it enabled an assessment of the intralaboratory reproducibility while also assessing the potential value of using ten animals of each sex per group instead of using the standard five animals of each sex per group stipulated by the current guideline. Tamoxifen was administered daily by gavage to groups of 7-week-old Wistar rats for at least 28 days at dose levels of 5, 30, or 200 microg/kg body weight. Additional parameters specified in the enhanced OECD Test Guideline 407 were spermatozoa enumeration and morphology of the cauda epididymis, hormonal analysis of the thyroid-stimulating hormone (TSH), triiodothyronine (T3) and thyroxine (T4) levels, monitoring of the estrous cycle during week 4 of treatment to ensure females were in diestrus on the day of terminal sacrifice, organ weight of ovary, uterus, thyroid gland, prostate gland (ventral and dorsolateral parts), seminal vesicles with coagulation glands and pituitary gland, and microscopic investigation of the pituitary gland, vagina, mammary gland, seminal vesicles with coagulating glands, epididymis, and prostate gland (ventral and dorsolateral parts). Overall, 200 microg/kg per day was considered to be the Maximum Tolerated Dose (MTD) in both sexes, resulting in a marked reduction of body weight gain, together with slight effects on clinical signs, hematology, plasma chemistry, and microscopic changes in some endocrine tissues. Five micrograms per kilogram per day represented the No Observed Adverse Effect Level (NOAEL) in males and the No Observed Effect Level (NOEL) in females. At the intermediate dose level (30 microg/kg per day), the current OECD Test Guideline 407 was appropriate to detect the specific endocrine-related changes induced by tamoxifen in females, based on the histopathology findings observed in the ovary and the uterus. The additional parameters which were found to be changed in females (thyroid hormone levels, ovary and uterus weights, and histopathology of vagina) provided supplementary information further confirming tamoxifen-mediated endocrine effects. In males, when data from the current Test Guideline 407 were considered at the intermediate dose level, specific endocrine effects were only indicated on the basis of the histopathology findings observed in the prostate gland. The additional parameters examined which were found to be changed (prostate gland and seminal vesicle weights, and histopathology of seminal vesicle and mammary gland) were necessary to confirm the specific tamoxifen-mediated endocrine effects. Hence, amongst the additional parameters contained in the enhanced OECD Test Guideline 407, organ weights and histopathological examinatio...

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“…There are partial agonistic effects associated with tamoxifen binding at the ER, especially at low doses of estradiol (34), which may be able to substitute for missing estrogen (35). In addition, there was a slight, although not statistically significant, overrepresentation of ER-negative breast cancer incidence in the tamoxifen group of the NSABP Breast Cancer Prevention P-1 Trial (1).…”

Section: Neu-induced Retroviral Rat Mammary Carcinogenesis Modelmentioning

confidence: 99%

Neu-Induced Retroviral Rat Mammary Carcinogenesis: A Novel Chemoprevention Model for Both Hormonally Responsive and Nonresponsive Mammary Carcinomas

et al. 2006

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Clinically relevant animal models of mammary carcinogenesis are crucial for the development and evaluation of new breast cancer chemopreventive agents. The neu-induced retroviral rat mammary carcinogenesis model is based on the direct in situ transfer of the activated neu oncogene into the mammary epithelium using a replication-defective retroviral vector. The resulting mammary carcinomas in intact WistarFurth rats exhibit a mixed hormonal response in the same proportion as has been observed in women. In intact rats, f50% of mammary carcinomas can be prevented by tamoxifen treatment. In ovariectomized animals, the mammary carcinomas are hormonally nonresponsive and cannot be prevented by tamoxifen. We evaluated the efficacy of retinoic X receptor-selective retinoids (rexinoids) in this novel model of mammary carcinogenesis. The rexinoids LG100268 and bexarotene (LG1069, Targretin) were highly efficacious in the prevention of neu-induced mammary carcinomas. Dietary LG100268 at 100 mg/kg diet decreased tumor multiplicity by 32% (P = 0.0114) in intact rats and 50% (P < 0.0001) in ovariectomized rats. Bexarotene treatment at a dose of 250 mg/kg diet was associated with reductions in tumor multiplicity of 84% (P < 0.0001) and 86% (P < 0.0001) in intact and ovariectomized animals, respectively. In addition to tumor multiplicity, proliferation and apoptosis were modulated by bexarotene treatment independently of estrogen signaling. The neu-induced retroviral rat mammary carcinogenesis model represents a valuable addition to existing rodent chemoprevention models. The model is useful for assessing the efficacy of chemopreventive agents, specifically those compounds that target hormonally nonresponsive tumors. (Cancer Res 2006; 66(13): 6884-91)

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An evaluation of tamoxifen as a partial agonist by classical receptor theory — An explanation of the dual action of tamoxifen

Cited by 41 publications

References 11 publications

Estrogen and Tamoxifen Modulate Cerebrovascular Tone in Ovariectomized Female Rats

Estrogen and Tamoxifen Modulate Cerebrovascular Tone in Ovariectomized Female Rats

Tamoxifen: 28-day oral toxicity study in the rat based on the Enhanced OECD Test Guideline 407 to detect endocrine effects

Neu-Induced Retroviral Rat Mammary Carcinogenesis: A Novel Chemoprevention Model for Both Hormonally Responsive and Nonresponsive Mammary Carcinomas

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