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Query: DrugBank:APRD00345 (ICI)
 5,388 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Most oral contraceptives (OC) contain a progestin in combination with an estrogen, and the progestin component in OC includes one of the following 19-nortestosterone derivatives: norethynodrel; norethindrone; or norgestrel (levonorgestrel). It is well known that estrogens promote the growth of breast cancer. However, progestins have recently also been implicated in the development of breast cancer. We have compared and contrasted the ability of synthetic progestins to stimulate the proliferation of cultured human breast cancer cells and examined their possible mechanism of action. We found that some progestins used in OC were able to stimulate the growth of estrogen receptor-positive (ER+) MCF-7 and T47DA18 human breast cancer cells but not ER- MDA-MB-231, BT-20, and T47DC4 human breast cancer cells. However, two other progestins, MPA and R5020, which are not used in OC, were either not able to stimulate or only slightly stimulated growth. The potency of norethynodrel [median effective dose (EC50) = 4 x 10(-8) M] and norethindrone (EC50 = 3 x 10(-8) M) was greater than norgestrel (EC50 = 2 x 10(-7) M) in MCF-7 cells. E2 (EC50 = 8 x 10(-13) M) was an even more potent stimulator of growth. More importantly, the progestin-induced growth stimulation was blocked by the antiestrogens 4-hydroxytamoxifen and ICI 164,384 but not the antiprogestin 17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)-17 alpha-(1-propynyl)-estra-4, 9-dien-3-one (RU486). To determine whether the proliferative action of progestins was mediated through the ER, cells were transfected with a chloramphenicol acetyltransferase reporter gene containing an estrogen response element derived from vitellogenin 2A gene. The progestins which stimulated the growth of breast cancer cells also increased chloramphenicol acetyltransferase activity. The induction of chloramphenicol acetyltransferase activity was blocked by the addition of the antiestrogens 4-hydroxytamoxifen and ICI 164,384 but not the antiprogestin RU486. This study provides direct evidence that the 19-nortestosterone derivatives in OC have estrogenic properties and suggests that activation of ER, but not progesterone receptor, is the growth-stimulatory mechanism for these synthetic progestins. Our results may help to explain the conflicting evidence linking OC and breast cancer risk. A rigorous evaluation of the "total" estrogenic potential of OC might produce a better correlation with breast cancer risk.
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PMID:Estrogenic potential of progestins in oral contraceptives to stimulate human breast cancer cell proliferation. 142

Breast cancers containing estrogen receptors are responsive to antiestrogen treatment and have a better prognosis than estrogen receptor-negative tumors. The loss of estrogen and progesterone receptors appears to be associated with a progression to less-differentiated tumors. We transfected the human estrogen receptor into the estrogen receptor-negative metastatic breast cancer cell line MDA-MB-231 in an attempt to restore their sensitivity to antiestrogens. Two stable sublines of MDA-MB-231 cells (HC1 and HE5) expressing functional estrogen receptors were studied for their ability to grow and invade in vitro and to metastasize in athymic nude mice. The number and size of lung metastases developed by these two sublines in ovariectomized nude mice was not markedly altered by tamoxifen but was inhibited 3-fold by estradiol. Estradiol also significantly inhibited in vitro cell proliferation of these sublines and their invasiveness in Matrigel, a reconstituted basement membrane, whereas the antiestrogens 4-hydroxytamoxifen and ICI 164,384 reversed these effects. These results show that estradiol inhibits the metastatic ability of estrogen receptor-negative breast cancer cells following transfection with the estrogen receptor, whereas estrogen receptor-positive breast cancers are stimulated by estrogen, indicating that factors other than the estrogen receptor are involved in progression toward hormone independence. Reactivation or transfer of the estrogen receptor gene can therefore be considered as therapeutic approaches to hormone-independent cancers.
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PMID:Activation of estrogen receptor transfected into a receptor-negative breast cancer cell line decreases the metastatic and invasive potential of the cells. 145 45

Of the total number of breast cancers approx. 30-50% are hormone-dependent and estradiol is one of the main factors of cancerization. Consequently, the control of this hormone inside the cancer cell is of capital importance because it is well established that the inhibition of estradiol biosynthesis can have a positive effect on the evolution of the disease. The blockage of estradiol can be obtained by the action of anti-aromatases, anti-sulfatases, the control of the 17 beta-hydroxysteroid dehydrogenase activity or by the stimulation of the sulfotransferase which converted the estrogens in their sulfates. In breast cancer tissue estrone sulfate is quantitatively the most important source of estradiol. In the intact cell, estrone sulfatase activity is very intense in the hormone-dependent cell lines (e.g. MCF-7, T-47D) but very small activity is observed in the hormone-independent (e.g. MDA-MB-231, MDA-MB-436) cell lines. However, this activity became very strong after homogenization in the hormone-independent cells, suggesting the presence of repressive factor(s) for this enzyme or its sequestering in an inactive form, in the intact cells of these cell lines. In a series of previous studies it was found that in hormone-dependent cell lines different anti-estrogens: tamoxifen and derivatives, ICI 164,384, very significantly decrease the estradiol concentration originated from estrone sulfate, and recently it was observed that Decapeptyl (D-Trp6-gonadotropin-releasing hormone) in the presence of heparin can also decrease the conversion of estrone sulfate into estradiol. No significant effect was obtained in the presence of heparin or Decapeptyl alone. The estrone sulfatase activity can be inhibited by progesterone, the progestagen R-5020, and testosterone. In another series of recent studies the presence of very strong estrogen sulfotransferase activity has been shown in one breast cancer cell line, the MDA-MB-468. We can conclude that: (1) the control of estradiol concentration can be carried out in the breast cancer tissue itself; (2) estrone sulfate can play an important role in the bioavailability of estradiol in the breast cancer cell; and (3) as is the case for the aromatase, the control of: the estrogen sulfatase, estrogen sulfotransferase, and 17 beta-hydroxysteroid dehydrogenase can be new targets for therapeutic applications in breast cancer.
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PMID:Recent data on estrogen sulfatases and sulfotransferases activities in human breast cancer. 158 Sep 21

The effect of the anti-estrogens ICI 164,384 and tamoxifen on the estradiol (E2) concentration after incubation of estrone sulfate (E1-S) with different hormone-dependent (MCF-7 and T-47D) and hormone-independent (MDA-MD-231 and MDA-MB-436) mammary cancer cells, as well as the estrone sulfatase activity in these various cell lines, are presented. The anti-estrogen ICI 164,384 decreased very significantly the concentration of E2 after incubation of E1-S with MCF-7 (control, mean +/- SE: 100 +/- 24 pg/mg DNA; + ICI 164,384 [10(-6)M]: 7 +/- 2 pg/mg DNA). This effect was much more intense than with tamoxifen. A similar effect was observed with T-47D cells. However, no significant effect was observed in the hormone-independent cells. In the intact cell, estrone sulfatase activity was very intense in the hormone-dependent cells, but very small in the hormone-independent cells. However, this activity became very strong after homogenization in the hormone-independent cells. The data suggest that estrone sulfate can play an important role on the bioavailability of E2 in hormone-dependent breast cancer, and that understanding the control of estrone sulfatase activity can open new knowledge of the estrogen responses and new possibilities of therapeutic application in breast cancer.
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PMID:Estrone sulfatase activity and effect of antiestrogens on transformation of estrone sulfate in hormone-dependent vs. independent human breast cancer cell lines. 191 12

The cathepsin D gene is differentially regulated by estrogens in hormone responsive breast cancer cells, by progestins in normal human endometrium and is highly expressed but not regulated by these steroids in estrogen (RE)- and progesterone receptor (RP)-negative breast cancer cells. We have stably transfected the RE-negative breast cancer cell line MDA-MB 231 and the Hela cell line with an expression vector for the human RE. The endogenous cathepsin D which is constitutively expressed was further stimulated by estradiol. However, the growth of both cell lines was not stimulated by estradiol and could not be inhibited by the antiestrogen ICI 164,384. By contrast, the cathepsin D gene in the estrogen responsive Ishikawa endometrial cancer cell line was unresponsive to estrogen or to progesterone even following stable transfection of expression vectors for the RP (both A and B isoforms). We conclude that the cathepsin D gene is potentially responsive to estrogens in MDA-MB 231 and Hela cells, which therefore express all of the transcriptional machinery (except the RE) necessary for this regulation. By contrast, cathepsin D remains unresponsive to estrogen and progesterone in Ishikawa cells. The cathepsin D gene is one of the first examples of an endogenous steroid responsive gene which can be controlled by steroids following stable transfection of a steroid receptor.
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PMID:Hormonal regulation of cathepsin D following transfection of the estrogen or progesterone receptor into three sex steroid hormone resistant cancer cell lines. 195 26

The biological response on proliferation and progesterone receptor (PR) of the anti-estrogen ICI 164,384 [N-n-butyl-N-methyl-11-(3,17 beta-dihydroxyestra-1,3,5(10-trien-7 alpha-yl))-undecanamide] was studied in different mammary cancer cell lines. In the hormone-dependent cancer cell lines (MCF-7 and T-47D) this anti-estrogen significantly decreased cell proliferation, but to reduce 50% of the growth in the MCF-7 cells a very low concentration (10(-9) M) is necessary. Similar effects in the T-47D cell are obtained with a dose of 100-1000 times (10(-6)-10(-7) M). The stimulatory effect in cell proliferation induced by estradiol is also inhibited by ICI 164,384 in both cell lines. This anti-estrogen has no effect on proliferation in the anti-estrogen resistant cell line LY-2, or in the hormone-independent cell line MDA-MB-436. Studies on thymidine incorporation correlate with the effect on cell proliferation. ICI 164,384 also blocks the stimulatory effect on progesterone receptor provoked by estradiol in MCF-7 cells and in T-47D cells which contain high concentration levels of progesterone receptor ICI 164,384 significantly decreases the PR concentrations in both the non-treated and estradiol-treated cells. It is concluded that ICI 164,384 is a full antagonist in the hormone-dependent breast cancer cells, but it has no effect in the anti-estrogen-resistant or in hormone-independent cell lines.
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PMID:Biological response of the anti-estrogen ICI 164,384 in human hormone-dependent and hormone-independent mammary cancer cell lines. 232 82

Different estrogen-3-sulfates (estrone-3-sulfate, estradiol-3-sulfate, and estriol-3-sulfate) can provoke important biologic responses in different mammary cancer cell lines; there is a significant increase in progesterone receptor. However, no significant effect was observed with estrogen-17-sulfates. The reason for the biologic response of estrogen-3-sulfates is that these sulfates are hydrolyzed, and no sulfatase activity for C17-sulfates is present in these cell lines. [3H]-Estrone sulfate is converted in a very high percentage to estradiol (E2) in different hormone-dependent mammary cancer cell lines (MCF-7, R-27, and T47D), but very little or no conversion was found in hormone-independent mammary cancer cell lines (MDA-MB-231 and MDA-MB-436). Different antiestrogens (tamoxifen and its derivatives) and another potent antiestrogen, ICI 164,384, significantly decrease the concentration of estradiol after incubation of estrone sulfate with the different hormone-dependent mammary cancer cell lines. No significant effect in the uptake and conversion of estrone sulfate was observed in hormone-independent mammary cancer cell lines. The data indicate that sulfatase activity for estrone sulfate is very low in the hormone-independent cell lines; however, comparative kinetic studies carried out after homogenization of MCF-7 and MDA-MB-436 cells show that sulfatase activity is similar, suggesting different mechanisms in the hydrolysis of estrone sulfate in hormone-dependent and hormone-independent cell lines. Progesterone also provokes a significant decrease in uptake and in estradiol levels after incubation of [3H]-estrone sulfate with the MCF-7 cell line. It is concluded that estrogen sulfates can play an important role in the biologic response of estrogens in breast cancer and that control of sulfatase and 17-hydroxysteroid dehydrogenase activities are key steps in the concentration and ability of estradiol in the mammary cancer cell line.
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PMID:Metabolism and biologic response of estrogen sulfates in hormone-dependent and hormone-independent mammary cancer cell lines. Effect of antiestrogens. 237

Estrogen sulfates are quantitatively the most important form of circulating estrogens during the menstrual cycle and in the post-menopausal period. Huge quantities of estrone sulfate and estradiol sulfate are found in the breast tissues of patients with mammary carcinoma. It has been demonstrated that different estrogen-3-sulfates (estrone-3-sulfate, estradiol-3-sulfate, estriol-3-sulfate) can provoke important biological responses in different mammary cancer cell lines: there is a significant increase in progesterone receptor. On the other hand, no significant effect was observed with estrogen-17-sulfates. The reason for the biological response of estrogen-3-sulfates is that these sulfates are hydrolyzed, and no sulfatase activity for C17-sulfates is present in these cell lines. [3H]Estrone sulfate is converted in a very high percentage to estradiol (E2) in different hormone-dependent mammary cancer cell lines (MCF-7, R-27, T-47D), but very little or no conversion was found in the hormone-independent mammary cancer cell lines (MDA-MB-231, MDA-MB-436). Different anti-estrogens (tamoxifen and derivatives) and another potent anti-estrogen: ICI 164,384, decrease the concentration of estradiol very significantly after incubation of estrone sulfate with the different hormone-dependent mammary cancer cell lines. No significant effect was observed for the uptake and conversion of estrone sulfate in the hormone-independent mammary cancer cell lines. Progesterone provokes an important decrease in the uptake and in estradiol levels after incubation of [3H]estrone sulfate with the MCF-7 cells. It is concluded that in breast cancer: (1) Estrogen sulfates can play an important role in the biological response of estrogens; (2) Anti-estrogens and progesterone significantly decrease the uptake and estradiol levels in hormone-dependent mammary cancer cell lines; (3) The control of the sulfatase and 17 beta-hydroxysteroid dehydrogenase activities, which are key steps in the formation of estradiol in the breast, can open new possibilities in the treatment of hormone-dependent mammary cancer.
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PMID:Importance of estrogen sulfates in breast cancer. 256 May 11

Estrone sulfate (E1-S) is quantitatively the main estrogen in human breast cancer tissue. This sulfate is converted with a great yield into estradiol (E2) in different hormone-dependent mammary cancer cell lines (MCF-7, R-27, T-47D). In opposition, there is small or no conversion in the hormone-independent cell lines (MDA-231 and MDA-436). The anti-estrogen tamoxifen blocks the conversion of E1-S to E2 in the MCF-7 and R-27 lines but not in the T-47D cell line. A new anti-estrogen: ICI 164,384 is also very active to block this conversion. In conclusion, the most probable way of action of the antiestrogen in through the competitive binding to the estrogen receptor; however recent date suggests other possible pathways.
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PMID:[Cancer of the breast, mechanism of action of anti-estrogens]. 305 88

Structural analogs of the nonsteroidal antiestrogen tamoxifen, in which the basic dimethylaminoethoxy side chain was either absent or replaced with a variety of nonbasic side chains, were examined for their ability to inhibit the proliferation of a hormonally responsive cell line, MCF 7 human breast cancer. The degree of inhibition was compared with relative binding affinities for the estrogen receptor (RE) and a microsomal antiestrogen binding site (AEBS). All modifications resulted in loss of detectable affinity for AEBS. Replacement of the basic side chain of tamoxifen with a series of nonbasic side chains reduced affinity for RE by 78-93% except in the case of 1-(4-(1,2-diphenylbut-1-enyl)phenyl)-2,3-butanediol (ICI 145-680) where affinity was unchanged. When the basic side chain of tamoxifen was replaced by a hydroxyl group, to form the estrogenic analog ICI 141389 (Metabolite E), affinity for RE was reduced by 39%. ICI 141389 was a very weak inhibitor of MCF 7 cell growth, showing no significant growth inhibition at concentrations less than 10 microM. Despite the fact that ICI 145680 and tamoxifen had identical affinities for RE, ICI 145680 was a significantly weaker growth inhibitor than tamoxifen over the concentration range studied, i.e. 0.1-20 microM. Differences in potency were greatest at concentrations greater than 7.5 microM where the effects were not reversed by estradiol and where cytotoxicity played a major role in the decrease in cell numbers induced by tamoxifen. Like tamoxifen, ICI 145680 demonstrated both estrogen-reversible (at concentrations between 0.5-7.5 microM) and estrogen-irreversible (10-20 microM) inhibition of MCF 7 cell proliferation which was associated with a concentration-dependent accumulation of cells in the G0/G1 phase of the cell cycle. In contrast to tamoxifen, however, ICI 145680 appeared not to possess cytotoxic activity. Whereas ICI 145680 was without effect on proliferation of the RE negative human breast cancer cell line, MDA-MB-330, at doses less than 20 microM, tamoxifen inhibited growth at concentrations greater than 5 microM, but with changes in cell cycle kinetic parameters that were markedly different from those seen in RE positive cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential effects of tamoxifen and analogs with nonbasic side chains on cell proliferation in vitro. 397 98


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