• Archives of Pharmacal Research
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• v.20 no.6
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• pp.579-585
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• 1997

To gain further insight into the mechanism of action of antiestrogens, we examined the interaction of antiestrogen with the estrogen receptor system and with estrogen- noncompetable antiestrogen binding sites. In addition to binding directly to the estrogen receptor, antiestrogens can be found associated with binding sites that are distinct from the estrogen receptor. In contrast to the restriction of estrogen receptors to estrogen target cells, such as those of uterus and mammary glands, antiestrogen binding sites are present in equal amounts in estrogen receptor-positive and -negative human breast cancer cell lines, such as MCF-7, T47D, and MDA-MB-231 that differ markedly in their sensitivity to antiestrogens. In order to gain greater insight into the role of these antiestrogen binding sites in the action of antiestrogens, we have examined the biopotency of different antiestrogens for the antiestrogen binding sites and that is CI628 > tamoxifen > trans-hydroxy tamoxifen > CI628M > H1285 > LY117018. This order of affinities does not parallel the affinity of these compounds for the estrogen receptor nor the potency of these compounds as antiestrogens. Indeed, compounds with high affinity for the estrogen receptor and greatest antiestrogenic potency have low affinities for these antiestrogen binding sites. Antiestrogenic potency correlates best with estrogen receptor affinity and not with affinity for antiestrogen binding sites. In summary, our findings suggested that interaction with the estrogen receptor is most likely the mechanism through which antiestrogens evoke their growth inhibitory effects.

• Archives of Pharmacal Research
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• v.20 no.6
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• pp.572-578
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• 1997

To gain further insight into how antiestrogens modulate cell function, the effects of antiestrogen on cell proliferation were studied in human breast cancer cells. We examined the effects of trans-tamoxifen on the proliferation of three human breast cancer cell lines that differed in their estrogen receptor contents. Trans-tamoxifen $(1{\mu}M)$ markedly inhibited the estrogen stimulated proliferation of MCF-7 human breast cancer cells that contained high levels of estrogen receptor $(1.15{\pm}0.03 pmole/mg protein)$ over that of control. In T47D cells that contained low levels of estrogen receptor $(0.23{\pm}0.05 pmole/mg protein)$, trans-tamoxifen $(1{\mu}M)$ showed minimal inhibition of estrogen stimulated cell proliferation over that of control. MDA-MB-231 cells, that contained no detectable levels of estrogen receptors, had their growth unaffected by trans-tamoxifen treatment. These results showed their sensitivity to growth inhibition by antiestrogen conrrelated well with their estrogen receptor content. Also we examined the effect of antiestrogen on cellular progestrone receptor level as well as plasminogen activator activity in MCF-7 cells. Trans-tamoxifen $(1{\mu}M)$ showed maximal inhibition of estrogen stimulated progestrone receptor level as well as plasminogen activator activity in MCF-7 cells that were stimulated by estrogen. It is not clear whether these inhibitions of progestrone receptor and plasminogen activator activity by estrogen are related to the antiestrogen inhibition of cell proliferation of MCF-7 cells. From the results of this study, it is clearly demonstrated that trans-tamoxifen is an antiestrogen in MCF-7 human breast cancer cells. Our data suggest that the biological effectiveness of trans-tamoxifen appear to result from its affinity of interaction with the estrogen receptor.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1993.04a
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• pp.100-100
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• 1993

Antiestrogen은 에스트로젠 의존성 유방암 치료에 사용되는 약물로써 표적 세포 내에서 에스트로젠 수용체와 작용하여 세포 증식 억제 작용을 나타내고 동시에 에스트로젠 수용체와는 구분되는 소포체 분획의 antiestrogen specific binding site (AEBS) 와도 결합을 하는 것으로 알려져 있다. 그러나, 아직 이 AEBS의 생리적 또는 약리적 기능은 밝혀져 있지 않다. 따라서 본 실험에서는 AEBS의 기능을 조사하기 위하여 cytochrome P45O III 효소군과 AEBS와의 관계를 자옹 백서를 이용하여 면역 화학 반응 실험 및 경쟁적 결합 반응 실험을 하였고, 그 결과는 다음과 같다. 1) AEBS에 대해서 SKF-525A와 metyrapone은 결합 능력을 나타내었다. 2) 자성쥐에서는 주령이 증가함에 따라 cytochrome P450양이 감소하였다. 3) 자옹성쥐 모두에서 phenobarbital 처치에 의해 cytochrome P450 III 효소양이 증가하였고, AEBS도 증가하였다. 4) 웅성쥐에서는 testosterone에 의하여 AEBS가 증가하였다. 5) 자웅성쥐 모두에 tamoxifen 관류시 cytochrome P450 III 효소양이 증가하였고 estradiol과 병용 관류시에는 tamonifen 단독 관류시보다 감소하였다. 이상의 결과에서 tamoxifen이 cytochrome P450 III을 유도할 수 있는 것으로 사료되며 cytochrome P450 III 효소군과 안티에스트로젠 결합부위와 밀접한 관련이 있는 것으로 생각된다.

• Archives of Pharmacal Research
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• v.16 no.4
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• pp.276-282
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• 1993

This study has been undertaken to examine the effect of 3-methylcholanthrene (3MC) on rat uterine growth and to understand the mechanism of action of 3MC in rat uterus. After diethylstilbesterol(DES) or tamoxifen(TAM) or 3MC or DES plus TAM or DES plus 3MC was administered into immature female rats, uterine weight over corn oil-treated uteri. 3MC treatment had no effect on uterine weight but, DES stimulated uterine weight was inhibited by 3MC concomitant tratment. While TAM alone treatment showed slight increase in uterine wieght, inhibited uterine growth simulated by DES when it was adiministrated with DES condirect binding assay with $[^3H]$ estradiol and the relative binding affinities of 3MC and TAM were estimated by competetion assy. Estradiol tumed out to have high affinity for rat uterine estrogen receptor (kd = 0.4 nM). The relative binding affinities of TAM and 3MC were 1% and 4.7% that of DES for rat uterine estrogen receptor, respectively. 3MC was shown to have similar affinity for eat uterine estrogen receptor to that of TAM. Effects of DES 3MC and TAM administration in vivo on rat uterine estrogen recptor level were examined. It was confirmed that the estrogen, DES and antiestrogen, TAM decreased estrogen receptor levels from rat ulterus and also 3MC decreased rat uterine estrogen receptor level when rats were treated with DES, TAM and 3MC in vivo. Data indicates that 3MC acts as an antiestrogen mediated through estrogen receptor system.

• Journal of Embryo Transfer
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• v.4 no.1
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• pp.46-55
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• 1989

The effects of an antiprogesterone (RU 486) and an antiestrogen (tamoxifen) on ovulatory response and oocyte morphology were examined in pregnant mare serum gonadotropin (PMSG)-primed immatare female rats (28 days of age): a comparison has been made on two different regirnens primed with a "control" dose (4 IU) and a "superovulatory" dose (40 IU) of PMSG. Females for control control regimen received three consecutive injections of lmg RU486, lmg tamoxifen, or vehicle at 24, 36 and 48hr, and were killed at 72l'r after PMSG. Animals for superovalatory regimen received lmg RU486, 2.5mg tamoxifen, or vehicle fouowlag the injection schedule comparable to control regimen, and were killed at 60 and 72hr after PMSG. Compared to vehicle group, there was a significant reduction in ovulatory response as judged by the proportion of rats ovulating andi or by the mean number of oocytes per rat for each treatment of RU486 and tamoxifen in both regimens. The activity of tamoxifen in inhibiting the ovulatory response was greater in control, but less in superovulatory regimen than that of RU486 based on the dose employed for each antisteroid. In both regimens, RU 486 did not have any effect 6n the changes in the proportion of degenerate oocytes as well as ovarian weight, well tamoxifen treatment resulted in a marked promotion of oocyte degeneration as well as a great reduction in ovarian weight, compared to each parameter of vehicle group. RU486 treatment in each regimen did not alter the serum levels of any steroid hormones observed. Howerver, tamoxifen treatment was associated with significant increases in serum 17$\beta$-estradiol and decreases in progesterone in both regimens; also significant increases in androgens in superovulatory regimen. The results illustrate the relative inhibitory activity of RU486 and tamoxifen indicating major steroid hormone involved in PMSG-induced ovulation: 17$\beta$-estradiol for control and progesterone for superovulatory regimen. It also appears that tamoxifen-associated elevation of circulating 17$\beta$-estradiol andi or androgens could be in part, a contributing factor to the promotion of oocyte degeneration presumably by producing a hostile oviductal environment after ovulation.ent after ovulation.

• Proceedings of the Zoological Society Korea Conference
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• 2000.10a
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• pp.174.2-174
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• 2000

• Investigative Magnetic Resonance Imaging
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• v.19 no.1
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• pp.56-61
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• 2015

Adenosarcoma of the uterus is a rare biphasic tumor containing benign glandular epithelial and malignant mesenchymal components. The tumor has been reported to be associated with antiestrogen therapy, particularly tamoxifen, but there have been a few case reports with MRI. We present two cases of MRI findings of uterine adenosarcoma after antiestrogen therapy, tamoxifen and toremifene in breast cancer patients. The tumor presents as a large polypoid mass occupying the endometrial cavity, and may protrude into the vagina. On MRI, the tumor typically shows solid components with scattered small cysts and heterogeneous enhancement. These findings are not significantly different from conventional adenosarcoma.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1999.04a
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• pp.5-8
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• 1999

여성의 breast cancer의 1/3 의 경우가 hormone-dependent에 의한 것이다. 따라서 그 치료의 접근 방법으로써 estrogen receptor에 작용하거나, receptor-mediated gene trenscription을 저해하는 antiestrogen을 사용하는 것이 있다. Estrogen은 microsomal cytochrome P-450 enzyme complex system에 의해 androgen으로부터 생합성되는 hormone이며, estrogen product는 steroid product의 biosynthetic sequence의 마지막 단계에서 생산되고, aromatase는 이에 관여하는 enzyme으로써, aromatase를 선택적으로 저해하는 경우에 다른 steroid의 생산에 영향을 미치지 않고 estrogen 생산을 감소 시킬 수 있다. 이러한 관점에서, aromatase를 선택적으로 저해하는 것은 hormone-dependent breast cancer를 완화시킬 수 있는 가능성을 가진 cancer chernopreventive agents의 새로운 방법이라 할 수 있다.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.18
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• pp.8135-8140
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• 2016

Background: Cell cycle regulatory proteins are suitable targets for cancer therapeutic development since genetic alterations in many cancers also affect the functions of these molecules. Strobilanthes crispus (S. crispus) is traditionally known for its potential benefits in treating various ailments. We recently reported that an active sub-fraction of S. crispus leaves (SCS) caused caspase-dependent apoptosis of human breast cancer MCF-7 and MDA-MB-231 cells. Materials and Methods: Considering the ability of SCS to also promote the activity of the antiestrogen, tamoxifen, we further examined the effect of SCS in modulating cell cycle progression and related proteins in MCF-7 and MDA-MB-231 cells alone and in combination with tamoxifen. Expression of cell cycle-related transcripts was analysed based on a previous microarray dataset. Results: SCS significantly caused G1 arrest of both types of cells, similar to tamoxifen and this was associated with modulation of cyclin D1, p21 and p53. In combination with tamoxifen, the anticancer effects involved downregulation of $ER{\alpha}$ protein in MCF-7 cells but appeared independent of an ER-mediated mechanism in MDA-MB-231 cells. Microarray data analysis confirmed the clinical relevance of the proteins studied. Conclusions: The current data suggest that SCS growth inhibitory effects are similar to that of the antiestrogen, tamoxifen, further supporting the previously demonstrated cytotoxic and apoptotic actions of both agents.

• Biomolecules & Therapeutics
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• v.20 no.3
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• pp.256-267
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• 2012

Tamoxifen is a central component of the treatment of estrogen receptor (ER)-positive breast cancer as a partial agonist of ER. It has been clinically used for the last 30 years and is currently available as a chemopreventive agent in women with high risk for breast cancer. The most challenging issue with tamoxifen use is the development of resistance in an initially responsive breast tumor. This review summarizes the roles of ER as the therapeutic target of tamoxifen in cancer treatment, clinical values and issues of tamoxifen use, and molecular mechanisms of tamoxifen resistance. Emerging knowledge on the molecular mechanisms of tamoxifen resistance will provide insight into the design of regimens to overcome tamoxifen resistance and discovery of novel therapeutic agents with a decreased chance of developing resistance as well as establishing more efficient treatment strategies.