Antagonism of estrogen action with a new benzothiophene derived antiestrogen

Black, Larry J.; Jones, Charles D.; Falcone, Julie F.

doi:10.1016/0024-3205(83)90935-9

Cited by 235 publications

(87 citation statements)

References 6 publications

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“…For example, tamoxifen and toremifene, the SERMs for which the longest clinical experience is available, act as estrogen antagonists in breast tissue and as estrogen agonists in bone and endometrium (Hayes et al 1995, Tomas et al 1995. On the other hand, raloxifene, an agent currently used to prevent osteoporosis, behaves as an estrogen antagonist in both breast and endometrium (Black et al 1983, Fuchs-Young et al 1995. These differences in the activity of SERMs appear to be related to differences in their molecular structures (e.g.…”

Section: The Role Of Er Blockers In Breast Cancermentioning

confidence: 99%

Chemoprevention of breast cancer and the trials of the National Surgical Adjuvant Breast and Bowel Project and others.

Smith

Good²

2003

Endocrine-Related Cancer

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The idea of breast cancer prevention by hormonal means stemmed from the results of treatment trials, many of them carried out by the National Surgical Adjuvant Breast and Bowel Project (NSABP). Over the years, a number of NSABP treatment studies demonstrated that breast cancer recurrence was reduced in women with the disease who were given tamoxifen, a selective estrogen receptor (ER) modulator (SERM). Five subsequent tamoxifen prevention trials with this agent have shown a 48% reduction in ER-positive cancers, but no effect for ER-negative cancers, and an increase in endometrial cancer and thromboembolic events. The drug raloxifene, another SERM, originally examined as an osteoporosis agent, has also shown promise for the prevention of breast cancer, although, as with tamoxifen, the drug carries a risk for thromboembolic events. There is recent evidence in a large treatment trial that the aromastase inhibitor anastrazole, a 'pure anti-estrogen', holds promise as a breast cancer preventive agent. Longer follow-up and the testing of additional agents is required before these drugs can be used widely for prevention. In addition, future research should focus on the identification of at-risk women who can perhaps be targeted for specific prevention agents.

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Section: The Role Of Er Blockers In Breast Cancermentioning

confidence: 99%

Chemoprevention of breast cancer and the trials of the National Surgical Adjuvant Breast and Bowel Project and others.

Smith

Good²

2003

Endocrine-Related Cancer

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“…1) is a polyhydroxyphenyl benzothiophene antiestrogen that has low estrogen agonist activity in the rodent uterus (1). The compound originally referred to as Ly156758 or keoxifene was abandoned for development as a treatment for breast cancer (2), because its bioavailability was less than 2% administered dose (3).…”

mentioning

confidence: 99%

Structure-Function Relationships of the Raloxifene-Estrogen Receptor-α Complex for Regulating Transforming Growth Factor-α Expression in Breast Cancer Cells

Liu¹,

Park²,

Bentrem³

et al. 2002

Journal of Biological Chemistry

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Amino acid Asp-351 in the ligand binding domain of estrogen receptor ␣ (ER␣) plays an important role in regulating the estrogen-like activity of selective estrogen receptor modulator-ER␣ complexes. 4-Hydroxytamoxifen is a full agonist at a transforming growth factor ␣ target gene in situ in MDA-MB-231 human breast cancer cells stably transfected with the wild-type ER␣. In contrast, raloxifene (Ral), which is also a selective estrogen receptor modulator, is a complete antiestrogen in this system. Because D351G ER␣ allosterically silences activation function-1 activity in the 4-hydroxytamoxifen-ER␣ complex with the complete loss of estrogenlike activity, we examined the converse interaction of amino acid 351 and the piperidine ring of the antiestrogen side chain of raloxifene to enhance estrogen-like action. MDA-MB-231 cells were either transiently or stably transfected with Asp-351 (the wild type), D351E, D351Y, or D351F ER␣ expression vectors. Profound differences in the agonist and antagonist actions of Ral⅐ER␣ complexes were noted only in stable transfectants. The agonist activity of the Ral⅐ER␣ complex was enhanced with D351E and D351Y ER␣, but raloxifene lost its agonist activity with D351F ER␣. The distance between the piperidine nitrogen of raloxifene and the negative charge of amino acid 351 was critical for estrogen-like actions. The role of the piperidine ring in neutralizing Asp-351 was addressed using compound R1h, a raloxifene derivative replacing the nitrogen on its piperidine ring with a carbon to form cyclohexane. The derivative was a potent agonist with wild type ER␣. These results support the concept that the side chain of raloxifene shields and neutralizes the Asp-351 to produce an antiestrogenic ER␣ complex. Alteration of either the side chain or its relationship with the negative charge at amino acid 351 controls the estrogen-like action at activating function 2b of the selective estrogen receptor modulator ER␣ complex.Raloxifene (Ral) 1 (see Fig. 1) is a polyhydroxyphenyl benzothiophene antiestrogen that has low estrogen agonist activity in the rodent uterus (1). The compound originally referred to as Ly156758 or keoxifene was abandoned for development as a treatment for breast cancer (2), because its bioavailability was less than 2% administered dose (3). However, the recognition that raloxifene maintains bone density (4, 5) and inhibits mammary carcinogenesis in the rat (6, 7) illustrates the concept of selective estrogen receptor modulation. Raloxifene is used for the prevention of osteoporosis in postmenopausal women (8), and treatment is associated with a reduced incidence of breast cancer (9).Tamoxifen is the prototype selective estrogen receptor modulator (SERM) that is used clinically for the treatment and prevention of breast cancer (10, 11) with the ability to maintain bone density in postmenopausal women (12). However, tamoxifen therapy is also associated with estrogen-like effects in the uterus with an increased incidence of endometrial cancer (13). Raloxifene is currently being ...

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“…Trioxifene was developed as a potential competitor for tamoxifen but failed to demonstrate either increased efficacy in the treatment of metastatic breast cancer or decrease in serious side effects. In the wake of the discovery that tamoxifen was metabolically activated to 4-hydroxytamoxifen with high binding affinity for the ER (Figure 2) [70,94] a compound LY156758 or keoxifene was developed that had high binding affinity for the ER and did not have oestrogen-like activity in the uterus [95]. Keoxifene failed to become a breast cancer therapy and was abandoned in 1987.…”

Section: Figurementioning

confidence: 99%

Proven value of translational research with appropriate animal models to advance breast cancer treatment and save lives: the tamoxifen tale

Jordan

2015

Brit J Clinical Pharma

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Antagonism of estrogen action with a new benzothiophene derived antiestrogen

Cited by 235 publications

References 6 publications

Chemoprevention of breast cancer and the trials of the National Surgical Adjuvant Breast and Bowel Project and others.

Chemoprevention of breast cancer and the trials of the National Surgical Adjuvant Breast and Bowel Project and others.

Structure-Function Relationships of the Raloxifene-Estrogen Receptor-α Complex for Regulating Transforming Growth Factor-α Expression in Breast Cancer Cells

Proven value of translational research with appropriate animal models to advance breast cancer treatment and save lives: the tamoxifen tale

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