Pharmacodynamic and biological effects of anti-estrogens in different models

Pasqualini, Jörge R.; Sumida, C.; Giambiagi, N.

doi:10.1016/0022-4731(88)90013-1

Cited by 78 publications

(21 citation statements)

References 149 publications

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“…In vitro studies using recombinant human CYPs have also indicated a contribution of CYP 2C9 in the hydroxylation process of tamoxifen (20), although the findings seem inconclusive (18,21). The metabolite 4-hydroxytamoxifen (4OHtam) is highly potent because its affinity for the estrogen receptor (ER) is up to 140 times higher than tamoxifen in in vitro systems (22,23). However, serum concentrations of 4OHtam are only ϳ2% of the parent drug levels, whereas N-desmethyltamoxifen (NDtam) concentrations are about 1.5-2 times greater (8).…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen and Metabolite Concentrations in Serum and Breast Cancer Tissue during Three Dose Regimens in a Randomized Preoperative Trial

Kisanga

Gjerde

Guerrieri-Gonzaga

et al. 2004

Clinical Cancer Research

181

124

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Purpose: Both therapeutic and adverse effects of tamoxifen may be related to its tissue concentrations. We investigated concentrations of tamoxifen, 4-hydroxytamoxifen, Ndesmethyltamoxifen, and N-didesmethyltamoxifen in serum, normal breast, and breast cancer tissues during conventional dosage and two low-dose regimens. Furthermore we studied tamoxifen effects on the cancer proliferation marker Ki-67, and on sex hormone-binding globulin (SHBG).Experimental Design: From September 1999 to August 2001, 120 breast cancer patients were randomized to 20-, 5-, or 1-mg tamoxifen daily. We measured serum and tissue concentrations of tamoxifen and three metabolites after 28 days of treatment, and the changes between baseline and post-treatment levels of SHBG and Ki-67.Results: The median (range) tamoxifen concentrations (ng/ml) at doses of 1, 5, and 20 mg daily (n ‫؍‬ 38, 37, and 36) were 7.5 (2.9 -120.9), 25.2 (1.9 -180.9), and 83.6 (8.7-134.4) in serum, and 78.2 (35.9 -184), 272.3 (122-641), and 744.4 (208.6 -2556) in breast cancer tissue, respectively. Tamoxifen levels followed a dose-concentration relationship. The concentrations of tamoxifen and metabolites were related to each other. Serum and tissue concentrations of tamoxifen were associated with corresponding changes of SHBG levels, whereas changes of Ki-67 levels were not related. Conclusions:Estrogen agonistic effects of tamoxifen on SHBG decreased with lower dosage, whereas tamoxifen effects on Ki-67 expression did not change. This together with a >10-fold variation in serum tamoxifen concentrations and a serum to tissue concentration relationship suggest that tamoxifen treatment may be improved by administration of lower doses and therapeutic drug monitoring.

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Section: Introductionmentioning

confidence: 99%

Tamoxifen and Metabolite Concentrations in Serum and Breast Cancer Tissue during Three Dose Regimens in a Randomized Preoperative Trial

Kisanga

Gjerde

Guerrieri-Gonzaga

et al. 2004

Clinical Cancer Research

181

124

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“…Development of effective therapeutic and preventive approaches for breast cancer remains an issue, since conventional treatment by antiestrogens such as tamoxifen often leads to resistance in estrogen receptor-positive tumors (18), and chemotherapy of estrogen receptor-negative tumors is even less effective (19). Since there is a high incidence of vitamin D receptors (VDRs) in human breast cancer tumors (21,22), vitamin D 3 is an appealing candidate as a new therapeutic agent.…”

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confidence: 99%

Regulation of Transforming Growth Factor-β Type II Receptor Expression in Human Breast Cancer MCF-7 Cells by Vitamin D3and Its Analogues

Wu¹,

Fan²,

Li³

et al. 1998

Journal of Biological Chemistry

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In view of the tumor suppressor role of the transforming growth factor-␤ (TGF␤) type II receptor (RII), the identification and characterization of agents that can induce the expression of this receptor are of potential importance to the development of chemoprevention approaches as well as treatment of cancer. To date, the identification of exogenous agents that control RII expression has been rare. We demonstrated that proliferation of MCF-7 early passage cells (MCF-7 E), which express RII and are sensitive to TGF␤ growth inhibition activity, was significantly inhibited by vitamin D 3 and its analogue EB1089. In contrast, proliferation of MCF-7 late passage cells (MCF-7 L), which have lost cell surface RII and are resistant to TGF␤, was not affected by these two compounds. TGF␤-neutralizing antibody was able to block the inhibitory effect on MCF-7 E cells by these compounds, indicating that treatment induced autocrine-negative TGF␤ activity. An RNase protection assay showed approximately a 3-fold induction of the RII mRNA, while a receptor cross-linking assay revealed a 3-4-fold induction of the RII protein. In contrast, there was no change in either RII mRNA or protein in the MCF-7 L cells. Transforming growth factor-␤ (TGF␤)1 comprises a family of hormone-like polypeptides that affects cell growth, adhesion, and differentiation (1). They act as growth inhibitors for most epithelial cells and some cancer cells. Two pathways are primarily involved in mediating effects of TGF␤ on cell growth and differentiation. One pathway involves blockade of cell cycle transit, while the other involves alteration of the extracellular matrix environment.TGF␤s elicit their effects by binding to cell surface receptors. Three major types of receptors have been shown to be present in most TGF␤-responsive cell lines. They are designated as type I (RI), type II (RII), and type III (RIII), respectively. RIII is a 280 -330-kDa glycoprotein that has no functional signaling domain but rather serves as a ligand storage protein and presents TGF␤ to the signaling receptors (2). RI and RII, which are glycoproteins of ϳ55 and 85 kDa, respectively, form a heteromeric receptor complex. Both are serine/threonine kinases, and each appears to be indispensable for TGF␤ signaling (3-5). The direct involvement of both RI and RII in conferring TGF␤ effects indicates that loss of either of the functional receptors would contribute to loss of autocrine TGF␤ activity. Loss of negative autocrine TGF␤ activity results in a growth advantage caused by an imbalance in positive and negative regulators, possibly leading to tumor formation and progression (6, 7). Recent evidence has shown a loss of RII is often associated with the failure to respond to autocrine and exogenous TGF␤. We have previously demonstrated that re-expression of this receptor in an RII-deficient breast cancer cell line (late passage MCF-7) leads to restoration of TGF␤ sensitivity and reduced malignancy in athymic nude mice (6). In addition, it has been shown that mutational inactivation of...

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“…It is considered to be the antihormonal treatment of choice for patients with advanced cancer, as well as for low-risk patients [2]. Tamoxifen exhibits both estrogen agonist and antagonist properties [1]. While tamoxifen is an estrogen antagonist in the breast [16], it is an estrogen agonist in the lower genital tract [17,18].…”

Section: Discussionmentioning

confidence: 99%

“…Tamoxifen is a nonsteroidal agent with estrogen agonist and antagonist properties [1]. Its estrogen antagonist properties have qualified tamoxifen as an important treatment modality for patients with breast cancer, especially those whose tumors are positive for estrogen receptors.…”

Section: Introductionmentioning

confidence: 99%

Torsion of a Functional Ovarian Cyst in a Premenopausal Patient Receiving Tamoxifen

Nasu¹,

Miyazaki²,

Kiyonaga³

et al. 1999

Gynecol Obstet Invest

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We report a case of torsion of an ovarian follicular cyst that developed during treatment with tamoxifen for breast cancer. A 40-year-old Japanese woman was admitted complaining of acute lower abdominal pain. Eight months earlier, she had undergone a partial mastectomy and local irradiation for ductal carcinoma of her left breast, estrogen receptor-positive stage I (T_1a N_1b M₀). The administration of tamoxifen, 20 mg/day, and doxifluridine, 600 mg/day, were started immediately postoperatively. Pelvic examination after admission revealed the left ovarian cyst and enlarged uterus. Transvaginal ultrasonography and computed tomography revealed a multilocular cystic mass in the pelvic cavity. The pathological diagnosis of the tumor after total hysterectomy and bilateral salpingo-oophorectomy was a typical follicular cyst with torsion and uterine leiomyoma. This ovarian cyst was believed to have developed during tamoxifen administration.

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Pharmacodynamic and biological effects of anti-estrogens in different models

Cited by 78 publications

References 149 publications

Tamoxifen and Metabolite Concentrations in Serum and Breast Cancer Tissue during Three Dose Regimens in a Randomized Preoperative Trial

Tamoxifen and Metabolite Concentrations in Serum and Breast Cancer Tissue during Three Dose Regimens in a Randomized Preoperative Trial

Regulation of Transforming Growth Factor-β Type II Receptor Expression in Human Breast Cancer MCF-7 Cells by Vitamin D3and Its Analogues

Torsion of a Functional Ovarian Cyst in a Premenopausal Patient Receiving Tamoxifen

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