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Clinical Breast Cancer Jan 2002This article provides an overview of the historical development, current research, clinical benefits, and potential future applications of the selective estrogen... (Review)
Review
This article provides an overview of the historical development, current research, clinical benefits, and potential future applications of the selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene. The understanding of the mechanism of action of SERMs led not only to the development of tamoxifen, the first widely used antiestrogen for breast cancer treatment, but also to its application as a chemopreventive agent. The SERM principle of antiestrogenic actions in the breast but estrogenlike actions in bone is reviewed in clinical practice through analysis of the current applications and the potential for expanding the role of SERMs. The current view of the molecular mechanism of SERM action is summarized to identify potential target sites for future research. The clinical success of tamoxifen and raloxifene for the prevention and treatment of breast cancer and osteoporosis, respectively, has encouraged the development of a range of new agents that target breast cancer, osteoporosis, coronary heart disease, and endometrial safety.
Topics: Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cinnamates; Drug Design; Forecasting; Humans; Molecular Biology; Piperidines; Pyrrolidines; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Stilbenes; Tamoxifen; Tetrahydronaphthalenes; Thiophenes; Toremifene; Treatment Outcome
PubMed: 11899358
DOI: 10.3816/cbc.2002.n.002 -
Cancer Research Aug 1997Although temporary benefits of tamoxifen therapy are observed in up to 40% of women with breast cancer, this compound, which is known to possess mixed estrogenic and... (Comparative Study)
Comparative Study
Blockade of the stimulatory effect of estrogens, OH-tamoxifen, OH-toremifene, droloxifene, and raloxifene on alkaline phosphatase activity by the antiestrogen EM-800 in human endometrial adenocarcinoma Ishikawa cells.
Although temporary benefits of tamoxifen therapy are observed in up to 40% of women with breast cancer, this compound, which is known to possess mixed estrogenic and antiestrogenic activities, has been associated with increased risk of endometrial carcinoma. This study compares the effects of the novel nonsteroidal pure antiestrogen EM-800 and related compounds with those of a series of antiestrogens on the estrogen-sensitive alkaline phosphatase (AP) activity in human endometrial adenocarcinoma Ishikawa cells. Exposure to increasing concentrations of up to 1000 nM EM-800 or its active metabolite EM-652 alone failed to affect basal AP activity. In contrast, incubation with 10 nM (Z)-4-OH-tamoxifen, (Z)-4-OH-toremifene, droloxifene, or raloxifene increased the value of this estrogen-sensitive parameter by 3.3-, 3.5-, 2.2-, and 1.6-fold, respectively, a stimulatory effect that was completely reversed by simultaneous exposure to 30 nM EM-800. Moreover, the stimulation of AP activity induced by 1 nM 17beta-estradiol was completely reversed by EM-800, EM-652, or ICI-182780, at the IC50 value of 1.98 +/- 0.23, 1.01 +/- 0.16, and 5.64 +/- 0.59 nM, respectively, whereas the partial blockade exerted by (Z)-4-OH-tamoxifen, (Z)-4-OH-toremifene, or raloxifene was observed at IC50 values of 13.5 +/- 3.80, 41.0 +/- 7.2, and 3.74 +/- 0.43 nM, respectively. Thus, as assessed by their activity in the human Ishikawa endometrial carcinoma cells, EM-800 and EM-652 are the most potent known antiestrogens in Ishikawa cells, and, most importantly, they are devoid of the estrogenic activity observed in these human endometrial cancer cells with (Z)-4-OH-tamoxifen, (Z)-4-OH-toremifene, droloxifene, and raloxifene.
Topics: Adenocarcinoma; Alkaline Phosphatase; Benzopyrans; Endometrial Neoplasms; Estradiol; Estrogen Antagonists; Female; Fulvestrant; Humans; Neoplasm Proteins; Piperidines; Propionates; Raloxifene Hydrochloride; Tamoxifen; Toremifene; Tumor Cells, Cultured
PubMed: 9270018
DOI: No ID Found -
Breast Cancer Research and Treatment Jul 2012Novel agents for the endocrine therapy of breast cancer are needed, especially in order to take advantage of the multiple consecutive responses observed in metastatic...
Novel agents for the endocrine therapy of breast cancer are needed, especially in order to take advantage of the multiple consecutive responses observed in metastatic progressing breast cancer following previous hormone therapy, thus delaying the use of cytotoxic chemotherapy with its frequent poor tolerance and serious side effects. Acolbifene (ACOL) is a novel and unique antiestrogen which represents a unique opportunity to achieve the most potent and specific blockade of estrogen action in the mammary gland and uterus while exerting estrogen-like beneficial effects in other tissues, especially the bones. To better understand the specificity of action of ACOL, we have used Affymetrix GeneChips containing 45,000 probe sets to analyze 34,000 genes to determine the specificity of this compound compared to the pure antiestrogen fulvestrant, as well as to the mixed antagonists/agonists tamoxifen and raloxifene to block the effect of estradiol (E(2)) and to induce effects of their own on the genomic profile in the mouse mammary gland. The genes modulated by E(2) were those identified in two separate experiments and validated by quantitative real-time PCR (qPCR). Three hours after the single subcutaneous injection of E(2) (0.05 μg), the simultaneous administration of ACOL, fulvestrant, tamoxifen, and raloxifene blocked by 98, 61, 43, and 92 % the number of E(2)-upregulated genes, respectively. On the other hand, 70, 10, 25, and 55 % of the genes down-regulated by E(2) were blocked by the same compounds. Of the 128 genes modulated by E(2), 49 are associated with tumorigenesis while 22 are known to be associated with breast cancer. When used alone, ACOL modulated the smallest number of genes also influenced by E(2), namely 4 %, thus possibly explaining potential utilities of this compound in breast cancer prevention and therapy.
Topics: Animals; Cluster Analysis; Estradiol; Estrogen Antagonists; Estrogens; Female; Fulvestrant; Gene Expression Regulation; Genes; Genes, Neoplasm; Mammary Glands, Animal; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Ovariectomy; Piperidines; Raloxifene Hydrochloride; Receptors, Estrogen; Tamoxifen; Transcription, Genetic; Transcriptome
PubMed: 22678160
DOI: 10.1007/s10549-012-2104-7 -
International Journal of Cancer May 2002EM-652 exerts pure antiestrogenic activity in the mammary gland and endometrium, while tamoxifen, the antiestrogen most widely used for the treatment of breast cancer,... (Comparative Study)
Comparative Study
Comparison of the effects of EM-652 (SCH57068), tamoxifen, toremifene, droloxifene, idoxifene, GW-5638 and raloxifene on the growth of human ZR-75-1 breast tumors in nude mice.
EM-652 exerts pure antiestrogenic activity in the mammary gland and endometrium, while tamoxifen, the antiestrogen most widely used for the treatment of breast cancer, exerts mixed antiestrogenic-estrogenic activity in these tissues. Our objective was to compare the agonistic and antagonistic effects of EM-652 with tamoxifen and 5 other antiestrogens on the growth of ZR-75-1 human breast xenografts in ovariectomized nude mice. During the 23 weeks of treatment at a daily oral dose of 50 microg, EM-652 was the only compound that decreased tumor size relative to pretreatment values, whereas the 6 other antiestrogens only decreased to various extents the progression rate stimulated by estrone. Under estrone stimulation, all groups of animals had more than 60% of their tumors in the progression category except for the EM-652-treated group, where only 7% of the tumors progressed. In the absence of estrone stimulation, progression was seen in 60%, 33%, 21% and 12% of tumors in the tamoxifen-, idoxifene-, toremifene- and raloxifene-treated groups, respectively, while only 4% of tumors progressed in the EM-652-treated group. The agonistic and antagonistic actions of each antiestrogen were also measured on endometrial epithelial cell thickness. Our present findings indicate that EM-652, in addition to being the most potent antiestrogen on human breast tumor growth, has no agonistic effect in breast and endometrial tissues. Since previous data have shown benefits of EM-652 on bone density and lipid profile, this compound could be an ideal candidate for chemoprevention of breast and uterine cancers, while protecting against osteoporosis and cardiovascular disease.
Topics: Animals; Breast Neoplasms; Cell Division; Cell Size; Cinnamates; Endometrium; Epithelial Cells; Estrogen Antagonists; Estrone; Female; Humans; Kinetics; Mice; Mice, Nude; Neoplasm Transplantation; Ovariectomy; Piperidines; Raloxifene Hydrochloride; Stilbenes; Tamoxifen; Toremifene; Tumor Cells, Cultured
PubMed: 11979444
DOI: 10.1002/ijc.10302 -
Cancer Research Sep 1999A naturally occurring mutation at amino acid 351 (D351Y) in the human estrogen receptor (ER) can change the pharmacology of antiestrogens. Raloxifene is converted from...
A naturally occurring mutation at amino acid 351 (D351Y) in the human estrogen receptor (ER) can change the pharmacology of antiestrogens. Raloxifene is converted from an antiestrogen to an estrogen, whereas the biological properties of the steroidal pure antiestrogen ICI 182,780 are not affected by the D351Y ER (Levenson, A. S., and Jordan, V. C. Cancer Res., 58: 1872-1875, 1998). We propose an assay system that can be used to classify antiestrogens by determining their ability to up-regulate transforming growth factor alpha (TGF-alpha) mRNA in MDA-MB-231 cells stably transfected with either wild-type or D351Y ER. The novel compound EM-800 and its active metabolite, EM-652, have been reported to be p.o. active nonsteroidal pure antiestrogens. Using the D351Y cell line, EM-652 is able to up-regulate TGF-alpha mRNA in a dose-dependent manner and to a similar extent as estradiol, whereas in the wild-type cell line, it acts as an antiestrogen. In addition, the pure antiestrogen ICI 182,780 is capable of inhibiting EM-652-induced TGF-alpha mRNA expression at the D351Y ER. In MCF-7 cells expressing wild-type ER, it has previously been shown that ICI 182,780 decreases ER only at the protein level. EM-652 treatment does not decrease ER protein levels to a similar extent as ICI 182,780 treatment, and, in addition, EM-652 has no effect on ER mRNA levels. In proliferation assays, EM-652 is as effective as raloxifene in inhibiting cell growth. From these studies, we conclude that the reason the pharmacology of EM-652 is similar to that of raloxifene is because they both fit the ER in the same manner, and their biology depends on an interaction of the antiestrogenic side chain with amino acid 351.
Topics: Benzopyrans; Cell Division; Estradiol; Estrogen Antagonists; Fulvestrant; Humans; Piperidines; Propionates; RNA, Messenger; Raloxifene Hydrochloride; Receptors, Estrogen; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha
PubMed: 10485477
DOI: No ID Found