Biomedical subjects

H Seeger

Publications and source records attributed to H Seeger.

At least 19 recordsLinked to original sources

PubMed2006

Urinary phytoestrogen excretion of rats bearing methylnitrosourea-induced mammary carcinoma in response to treatment with 2-methoxyestradiol.

The effect of treating mammary tumor-bearing rats with 2-methoxyestradiol (2-MeE2) on the urinary excretion of 12 phytoestrogens was investigated and compared with the changes in urinary excretion of estradiol metabolites. Alterations of excretion were registered for isoflavonoids, lignans and coumestans. However, due to large variations statistical significant differences were found only for two lignans, i.e. significant increases of enterodiol and matairesinol. Since the single components of phytoestrogens showed diverse alterations, excretions were expressed also by the ratio of total isoflavonoids to total lignans and compared with the estrogen ratios 2-hydroxyestrone to 16alpha-hydroxyestrone and A-ring to D-ring metabolites. The ratio of isoflavonoids to lignans was consistently decreased, whereas both ratios of estradiol metabolites were highly increased. The latter effect is probably due to demethylation of 2-methoxyestrone resulting in high catechol estrogen levels in urine. These results suggest that the high levels of catechol estrogens, produced by 2-MeE2 treatment, may have influenced the urinary excretion pattern of phytoestrogens.

2-Methoxyestradiol↗

PubMed2006

Is there a protective role of progestogens on the proliferation of human ovarian cancer cells in the presence of growth factors?

PURPOSE OF INVESTIGATION: The role of progestogens in the genesis of ovarian cancer remains unclear although a rather protective behaviour has been suggested. Epidemiological studies indicate a possible increase in the risk for combined estrogen/progestin as compared to estrogen alone. It is ambigious whether a difference exists within the various progestogens. Apart from sex steroids, growth factors play a crucial role in the genesis of ovarian cancer, although as yet little investigated. In the present study we have explored the effect of progesterone (P), medroxyprogesterone acetate (MPA) and norethisterone (NET) on the proliferation of human ovarian cancer cells alone and in the presence of growth factors. METHODS: For the experiments human ovarian cancer cells (OVCAR-3) were used. The progestogens were tested at the concentrations of 0.01 to 10 microM. The growth factor mixture consisted of EGF, FGF and IGF-I, each at a concentration of 10 pM. The incubation time was three or seven days. Proliferation rate was measured by an ATP-assay. RESULTS: After three days' incubation the growth factors induced an increase in the proliferation rate of about 50%. Progesterone alone did not show any significant change as compared to the control values, whereas NET and MPA elicited a significant increase at 1 and 10 microM and at 1 microM, respectively. In the presence of growth factors none of the progestogens was able to inhibit the proliferative stimulation. After seven days' incubation the growth factors still showed an increase of about 50%. MPA alone had an inhibitory effect at 10 microM, for NET and P no effects were observed. Again in the presence of growth factors no progestogen was able to show an inhibitory effect. CONCLUSION: Our results indicate that progestogens do not have a protective role on the growth of pre-existing ovarian cancer cells, at least in the presence of growth factors. Further investigations are worthwile to evaluate possible differences between the effect of the various progestogens.

Analysis of Variance↗

PubMed2006

The effect of estradiol metabolites and progestogens on the proliferation of human ovarian cancer cells.

The etiology of ovarian cancer appears to be associated with a long-term influence of estrogens. However, evidence is accumulating that certain estradiol metabolites may play a decisive role in the carcinogenesis of estrogen-dependent diseases. As yet little data are available on the association of estradiol metabolites and ovarian cancer. In vitro experiments revealed a potent stimulatory effect of certain metabolites on the proliferation of ovarian cancer cells, which is similar to or even stronger than the effect of their parent substance 17beta-estradiol. Therefore, the pattern of endogenous estradiol metabolism may play a role in defining ovarian cancer risk. This may be of importance in certain predisposed women who are treated with hormone therapy in the postmenopause. The role of progestogens in the genesis of ovarian cancer still remains unclear, rather a protective behaviour is suggested. Epidemiological studies indicate a possible increase in the risk for combined estrogen/progestin as compared to estrogen alone. It is ambigious whether a difference exists within the various progestogens. Apart from sex steroids growth factors play a crucial role in the genesis of ovarian cancer, although as yet little investigated. In vitro experiments indicate that progestogens do not have a protective role on the growth of pre-existing ovarian cancer cells, at least in the presence of growth factors. Further investigations are worthwile to evaluate possible differences between the effect of the various progestogens.

Cell Line, Tumor↗

PubMed2005

Different effects of estradiol and various antiestrogens on TNF-alpha-induced changes of biochemical markers for growth and invasion of human breast cancer cells.

In the field of estrogen therapy breast cancer risk is one of the most controversially discussed topic. Actually, the as yet largest placebo-controlled study, the Women's Health Initiative, rather showed a risk reduction, in contrast to observational studies. In the present study we have investigated the effect of estradiol on TNF-alpha-induced changes of various markers in human breast cancer cells and compare it with the effect of the antiestrogens tamoxifen and 2-methoxyestradiol. MCF-7 cells were used for the experiments, the incubation time was 96 h. TNF-alpha elicited a 3-4-fold increase of monocyte-attracting protein-1 (MCP-1) and interleukin-8 (IL-8) as compared to the control value, matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) were enhanced by 30 to 40%. E2 alone had no effect on MCP-1, slightly reduced the synthesis of MMP-9 and increased VEGF concentrations by about 20%. In combination with TNF, E2 induced a further stimulation of MCP-1, IL-8 and VEGF, whereby the MMP-9 synthesis was not changed. Tamoxifen and the endogenous estradiol metabolite 2-methoxyestradiol seem to be able to partly inhibit the action of TNF-alpha and estradiol. Our results suggest that estrogens may slightly increase tumor growth and spreading beyond the effect of chemokines such as TNF-alpha. However, the magnitude of this E2 effect seems to be marginal as compared to the effect of TNF-alpha alone. The risk of recurrence of breast cancer in patients taking hormone therapy after breast cancer may be slightly enhanced by estrogens, but seems mainly to be driven by the potency of still existing tumor cells to secrete chemokines which can stimulate tumor growth and spreading.

2-Methoxyestradiol↗

PubMed2005

Dose-dependent changes of the ratio of apoptosis to proliferation by norethisterone and medroxyprogesterone acetate in human breast epithelial cells.

OBJECTIVE: There is increasing evidence that adding progestogens to estrogen replacement therapy may do more harm than good; however, whether all progestogens act equally on breast cells is debatable. Apart from estrogens, mitogenic growth factors from stromal breast tissue are important in growth-regulation of breast cells, and may modify the response to progestogens. We investigated the effects of medroxyprogesterone acetate (MPA) as well as norethisterone (NET) in the presence of a growth factor mixture and/or estradiol in normal and cancerous human epithelial breast cells. METHODS: MCF10A cells (human epithelial, estrogen- and progesterone-receptor negative, normal breast cells), HCC1500 (human estrogen and progesterone receptor-positive primary breast cancer cells) and MCF-7 cells (human estrogen and progesterone receptor-positive metastatic breast cancer cell line) were used in the experiments. The cells were incubated with progestogens at concentrations of 10(-10) to 10(-6) M for 7 days and growth factors (GFs), estradiol (E2) alone and a combination of GFs + E2. Cell proliferation rate was measured by ATP assay. Apoptosis was measured by cell death assay. Ratios of cell death : proliferation were calculated from these results. RESULTS: In MCF10A cells growth factors elicited a decrease in the ratio of apoptosis to proliferation. This effect was further stimulated by the addition of MPA, whereas NET had no effect. In HCC cells growth factors and estradiol alone and in combination led to a reduction in the ratio. This effect could be partly reversed dose-dependently by the addition of MPA and NET, being more pronounced for MPA. Similar results were found for MCF-7 cells stimulated by estradiol. CONCLUSION: The results of our investigations demonstrate that there are differences between the two progestogens NET and MPA investigated with respect to their effects on normal and cancerous cells. By increasing the mitotic rate of normal epithelial cells, MPA may increase breast cancer risk in women when used in long-term treatment. In this respect NET reacts neutral. The mitosis of pre-existing cancerous cells may be partly inhibited by the addition of both progestogens. Thus, our results indicate that it is necessary to differentiate between normal and malignant breast cells concerning the assessment of progestogens as a risk factor for breast carcinogenesis.

Apoptosis↗

PubMed2005

Estradiol metabolites are potent mitogenic substances for human ovarian cancer cells.

PURPOSE OF INVESTIGATION: The etiology of ovarian cancer appears to be associated with a long-term influence of estrogens. However, evidence is accumulating that certain estradiol metabolites may play a decisive role in the carcinogenesis of estrogen-dependent diseases. In the present study we examined the effect of estradiol metabolites on the proliferation and apoptosis of human ovarian cancer cells in comparison to the effect of their parent substance. METHODS: The ovarian cancer cell line OVCAR-3 was used for the experiments. 17Beta-estradiol (E2), 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2) and 16alpha-hydroxyestrone (16-OHE1) were incubated for seven days in the concentration range of 0.01 nM to 10 nM. Proliferation and apoptosis were measured by commercially available assay kits. RESULTS: E2 enhanced proliferation rate and concomitantly reduced apoptotic rate of the ovarian cancer cells at physiological concentrations. 2-OHE2 had no significant effect, whereas 4-OHE2 elicited similar effects on proliferation and apoptotic rate as E2. The greatest proliferative and antiapoptotic effect was observed for 16-OHE1, the values being significantly different to the effects of E2. CONCLUSION: The pattern of endogenous estradiol metabolism may play a role in defining ovarian cancer risk. This may be of importance in certain predisposed women who are treated with hormone therapy in postmenopause.

Apoptosis↗

PubMed2004

Chemotherapy of breast cancer-additive anticancerogenic effects by 2-methoxyestradiol?

2-Methoxyestradiol (2ME) is an endogenous estradiol metabolite, which acts antiproliferative in various tumor cell lines independent of the hormone receptor status. We investigated whether combinations of 2ME with various chemotherapeutic or endocrine compounds may result in an additive effect on the proliferation of human breast cancer cells. The breast cancer cell lines MCF-7 (receptor-positive), BM (receptor-negative) and a MCF-7 line transfected with the aromatase gene were used. All cell lines were incubated in the concentration range of 0.8 microM to 25 microM with 2ME alone and in equimolar combinations with the following compounds: epirubicine, daunorubicine, paclitaxel, docetaxel, carboplatin, vinorelbine, 5-fluorouracil, mafosfamide and 4-OH tamoxifen. The effect of letrozole and 2ME alone and in equimolar combinations was tested in the concentration range of 0.6 to 1 microM. Proliferation was measured after 4 days using the ATP-chemosensitivity test. In MCF-7 cells 2ME in combination with 4OH-tamoxifen, epirubicine, docetaxel, 5-fluoprouracil, mafosfamide and carboplatin led to an additive effect. In BM cells only 2ME combined with 4OH-tamoxifen, daunorubicine and mafosfamide showed an additive action. Both letrozole and 2ME were nearly similar effective in inhibition of the aromatase gene. Here no additive effect was found. 2ME displayed antiproliferative actions in various human breast cancer cells. In addition 2ME was able to increase the antiproliferative property of certain antihormones and cytostatic substances. Furthermore 2ME exhibits a similar property as compared to letrozole in inhibiting the aromatase activity. Since 2ME was well tolerated in a recently conducted phase II trial in patients with refractory metastatic breast cancer, the combination of 2ME with chemotherapeutics or antihormones may offer a new clinically relevant treatment regimen.

2-Methoxyestradiol↗

PubMed2004

Class-specific pro-apoptotic effect of statins on human vascular endothelial cells.

Neonangiogenesis represents an important step in tumor development and propagation. Statins may have anticancerogenic potential by blocking vascular endothelial cell growth. The antiproliferative effect of four statins on human endothelial cells was compared, concomitantly delineating a possible pro-apoptotic process. All four statins tested, i. e. atorvastatin, fluvastatin, lovastatin, and simvastatin inhibited cell proliferation. Nearly complete blocking of cell proliferation was achieved at a concentration of 10 microM. We were able to demonstrate that the antiproliferative effect of the statins is not due to cytotoxicity but rather to an apoptotic effect as demonstrated by comparison of cytotoxicity assay and apoptosis assay. The apoptotic mechanism seems to involve caspases, since the statins significantly enhanced caspase activity at dosages of 10 and 20 microM. Further experiments revealed a downregulation of the pro-apoptotic protein Bcl-2. Our data indicate that statins may class-specific inhibit angiogenesis at high dosages which can contribute to prevention of tumor development and progression.

Apoptosis↗

PubMed2004

Inhibition of human breast cancer cell proliferation with estradiol metabolites is as effective as with tamoxifen.

The anti-estrogenic substance tamoxifen is effective in the adjuvant therapy applied in human breast cancer. Since it partly exhibits estrogenic activity and has serious side-effects, however, pure anti-estrogenic compounds are being sought. In our experimental study, we compared the anti-proliferative effect of estradiol and 13 endogenous estradiol metabolites on human breast cancer cells with the effect of tamoxifen. We used MCF-7 and MDA-MB 231, the well-established estrogen receptor-positive and -negative cell lines. 4-hydroxytamoxifen, the active metabolite of tamoxifen, estradiol and 13 estradiol metabolites were tested in concentrations ranging from 3.1 to 100 microM. Incubation time was 4 days and cell proliferation was measured by means of the ATP chemosensitivity test. 4-hydroxytamoxifen showed an IC50 value of 27 microM and 18 microM in MCF-7 and MDA-MB 231 cells, respectively. Estradiol and its metabolites were anti-proliferative in both cell lines. A few A-ring metabolites were more effective in inhibiting cell proliferation than D-ring metabolites and the parent substance 17beta-estradiol. 4-OHE1, 2-MeOE1 and 2-MeOE2 were as effective in both cell lines as tamoxifen. For the first time it has been demonstrated that endogenous estradiol metabolites are equally anti-proliferative as tamoxifen in the context of human breast cancer cells. Since some of these metabolites exhibit no estrogenic activity, they are likely to be valuable in clinical studies of chemoprevention and adjuvant therapy of breast cancer.

Breast Neoplasms↗

PubMed2004

Hormone therapy after endometrial cancer.

Endometrial carcinoma is listed under the absolute contraindications to hormone therapy (HT). According to current opinion, HT after stage I or II is still considered an option, and continuous combined oestrogen/progestogen replacement therapy (CCEPT) would be recommended. However, up to now, only observational studies have been put forward. Although none of these studies have established an increased rate of recurrence or mortality, alternatives such as phytopreparations and tibolone, or particular psychotherapeutic drugs, such as venlafaxine, should be considered for the relief of climacteric complaints. Progestogen-only therapy (PT) particularly has been considered. However, the currently discussed possible progestogen effects regarding an increased risk of breast cancer have to be taken into account. Indeed, the wider discussion about the gestagen effects regarding the risk of breast cancer is to be considered. Generally, after hysterectomy, at least for patients with cardiovascular risk factors, the preference today is to use low-dose oestrogen therapy (patches or gels) instead of CCEPT, and this is also now recommended for patients after endometrial cancer. This is to be noted because of the risk factors for endometrial carcinoma, such as hypertension, obesity, polycystic ovary syndrome (PCO) and diabetes mellitus. However, each form of HT should be only exceptionally recommended, and the patients must be informed about the risks that exist and the use of alternatives.

Endometrial Neoplasms↗

PubMed2004

Endogenous estradiol metabolism during treatment with oral contraceptives.

OBJECTIVE: Recent clinical studies indicate that an increase in D-ring estradiol metabolites over A-ring metabolites may be a risk factor for breast cancer. The present work was aimed to investigate the effect of oral contraceptives (OC) on the endogenous estradiol metabolism in premenopausal women. METHODS: Two studies were conducted, firstly comparing 2 different progestins, i.e. norethisterone and dienogest, each in combination with a constant ethinyl estradiol dosage (study A) and secondly comparing a single progestin, i.e. levonorgestrel in 2 ethinyl estradiol/progestin dosage combinations (study B). The main A- and D-ring metabolites, i.e. 2-OHE1 and 16-OHE1, were measured by enzyme immunoassay in 8-h night-urine collected before and after 3 cycles of OC administration. RESULTS: In study A, i.e. ethinyl estradiol plus dienogest or norethisterone acetate, the ratios of 16-OHE1 to 2-OHE1 before administration were 0.62 and 0.68, and after 3 months 0.31 and 0.54, respectively. The ratio after ethinyl estradiol and dienogest was significantly lower after treatment. In study B, i.e. ethinyl estradiol plus levonorgestrel (0.03 mg/0.15 mg and 0.02 mg/0.1 mg), the ratios before treatment were 0.71 and 0.75 for the higher and the lower dosages, respectively, which changed not significantly to 0.73 and 0.71 after 3 cycles. CONCLUSION: OCs containing norethisterone acetate, dienogest or levonorgestrel did not have a negative effect on estradiol metabolism, i.e. they did not elicit a higher D-ring metabolism, which is considered to increase breast cancer risk.

Adult↗

PubMed2004

Inhibitory effect of statins on the proliferation of human breast cancer cells.

OBJECTIVE: Long-term hormone therapy in the postmenopause is associated with a moderate increase in cardiovascular and breast cancer risk. Of great concern, therefore, is the question of how women with menopausal symptoms and enhanced cardiovascular risk can be treated. Evidence is growing that an estrogen/statin combination may be a good choice, since this combination seems to elicit additive beneficial effects on the lipid profile and on the vasculature. METHODS: In the present study, the effect of two statins on the proliferation of breast cancer cells in the presence and absence of estradiol was investigated. RESULTS: Atorvastatin and fluvastatin were able to inhibit the proliferation of MCF-7 cells in the absence of estradiol. This effect seems to depend on an apoptotic statin effect which may be mediated by the down-regulation of the anti-apoptotic protein Bcl-2 rather than up-regulation of Fas-L or p53. However, in the presence of estradiol the inhibitory effect of the statins was less pronounced. CONCLUSIONS: The present data indicate that statins may possess anticancerogenic properties concerning the development of breast cancer in postmenopausal women. Clinical trials are necessary to prove a beneficial statin effect on breast cancer risk when combined with long-term hormone therapy.

Anticholesteremic Agents↗

PubMed2004

'Pulsed' estradiol action can stimulate breast cancer cell proliferation.

PURPOSE OF INVESTIGATION: The newly available nasal estradiol application serum concentrations measure up to 10-fold higher compared to common hormone replacement therapy (HRT). Since this has only a short-time peak it has been suggested that breast cancer risk may be reduced, because of lower activation of the estradiol-receptor-transcription cascade. METHODS: Estradiol was tested at 10(-9) and 10(-8) M corresponding to the serum levels achieved with nasal application. In addition also comparable exposure times were investigated: Incubation time was 10, 20, 40, 60 and 180 min every day for four days, compared with continuous non-stop incubation for four days. The well-recognized MCF-7 breast cancer cell line was used. Cell proliferation was measured by the ATP-assay. RESULTS: Estradiol in concentrations achieved with 'pulsed' HT was able to elicit proliferation of MCF-7 cells already after an incubation time of ten minutes which correlates with the minimum of exposure time using nasal estradiol application. Compared to non-stop continuous estradiol added in the same high concentrations over four days no significant differences were observed. CONCLUSIONS: Short-time application of estradiol is able to stimulate breast cell proliferation to the same degree as continuously administered estradiol in high concentrations. Thus it remains questionable, if a 'pulsed' estradiol therapy may reduce breast cancer risk during HRT. Clinical studies are urgently needed to reveal the breast cancer risk during nasal estradiol application especially since this risk might be increased depending on the concentrations used.

Administration, Intranasal↗

PubMed2004

Influence of stroma-derived growth factors on the estradiol-stimulated proliferation of human breast cancer cells.

PURPOSE OF INVESTIGATION: Estradiol is the main proliferating substance for human epithelial breast cells. There is evidence that proliferation is also stimulated by growth factors mainly synthesized by the surrounding stroma. In the present in vitro study we have compared the proliferating activity of three growth factors alone and in combination with estradiol in human breast cancer cells. METHOD: As a cell model the well-recognized human breast cancer cell line MCF-7 was used. The growth factors tested were basic fibroblast growth factor (bFGF), epithelial growth factor (EGF) and insulin-growth factor-1 (IGF-I) at the concentrations 10(-10), 10(-9) and 10(-8) M alone and in equimolar combination with 10(-10) M estradiol. Cell proliferation was measured after seven days incubation by the ATP-assay. RESULTS: The growth factors alone significantly stimulated proliferation of MCF-7 cells in the tested concentration range. The increases were about 40% for EGF, between 40 and 60% for FGF and between 30 and 90% for IGF-I. The strongest proliferating factor was estradiol alone with values between 70 and 130%. For all three growth factors an additive effect was seen in combination with estradiol, which was greatest for IGF-I. CONCLUSION: These data indicate that estradiol is the strongest proliferating factor for human breast cancer cells. Therefore the predictive value of cell models using estradiol as a proliferative agent seems to be highly reliable. However, stromal influence by growth factors should not be disregarded, since proliferation of pre-existing malignant cells may be accelerated by the concomitant presence of estrogens and growth factors.

Breast Neoplasms↗

PubMed2004

Is the combination with 2-methoxyestradiol able to reduce the dosages of chemotherapeutices in the treatment of human ovarian cancer? Preliminary in vitro investigations.

PURPOSE OF INVESTIGATION: The endogenous estradiol metabolite, 2-methoxyestradiol (2ME), has been shown to be a potent inhibitor of cell growth and a strong anti-angiogenic substance. We investigated for the first time whether in vitro combinations of 2ME with various chemotherapeutic compounds may result in an additive inhibitory effect on the proliferation of human ovary cancer cells. METHOD: As a model two different human ovary cancer cell lines were used. All cell lines were incubated with equimolar concentrations of 2ME (0.8-25 microM) and the chemotherapeutics epirubicine, doxorubicine, paclitaxel, docetaxel, carboplatin, vinorelbine, 5-fluorouracil and mafosfamide. Proliferation was measured after four days using the ATP-chemosensitivity test. RESULTS: For both ovary cancer cell lines a significant additive effect of 2ME with epirubicine and carboplatin was observed at the lower concentration range of these chemotherapeutic substances. CONCLUSION: 2ME is able to enhance the antiproliferative activity of certain chemotherapeutics at pharmacological relevant concentrations. This estradiol metabolite is currently in a phase II trial in patients with refractary metastatic breast cancer and the tolerability has been shown to be very good. The combination of 2ME with chemotherapeutics may therefore offer a new clinically relevant treatment regimen for hormone-dependent cancer.

2-Methoxyestradiol↗

PubMed2003

The effect of endogenous estradiol metabolites on the proliferation of human breast cancer cells.

Evidence is accumulating that estradiol metabolites may be involved in carcinogenesis as some metabolites exert proliferative and others anti-proliferative properties on human cancer cells. The present study is the first to investigate the effect of 14 endogenous estradiol metabolites on the proliferation of the human breast cancer cell line, MCF-7, in comparison with the effect of the parent substance 17beta-estradiol with special concern on high pharmacological concentrations. The steroids were tested in the range from 10(-8) to 10(-5) M on MCF-7 cells which were incubated for nine days. Estradiol and almost all A-ring metabolites displayed biphasic reactions on cell proliferation, i.e. stimulatory at low concentrations and inhibitory at the highest concentration, 10(-5) M. The D-ring metabolites did not show such clear biphasic patterns, in most of them the stimulatory effect prevailed at the highest dosage used. The strongest inhibitory effect was seen for the A-ring metabolite 2-methoxyestradiol at the concentrations of 10(-6) and 10(-5) M and the strongest stimulatory effect was noted for the D-ring metabolite estriol at the same concentrations. The results indicate that some A-ring metabolites might be suitable for breast cancer treatment when used in high dosages. This is of special interest, since many of these metabolites have very weak estrogenic activity.

Breast Neoplasms↗

PubMed2003

Effects of tibolone on human breast cancer cells and human vascular coronary cells.

Tibolone is a synthetic progestin with estrogenic and progestogenic properties, used to alleviate menopausal syndromes and for osteoporosis prophylaxis in postmenopausal women. However, only little data are available on tibolone and breast cancer risk and on the effects of tibolone on the cardiovascular system. Therefore, in the present in vitro study, we investigated the effect of tibolone on the growth of the human breast cancer cell line, MCF-7, and on the direct effects of tibolone on the vasculature, i.e. human female coronary endothelial and smooth muscle cells. In the breast cancer cell experiments, tibolone was examined alone and in the presence of 0.1 nM estradiol in the concentration range from 0.001 microM to 1 microM. Tibolone lead to significant cell growth in the concentration range of 0.01 micro M to 1 microM and was not able to inhibit estradiol-induced proliferation at the concentrations of 0.01 microM and 0.1 microM. In the vascular endothelial cell culture experiments, tibolone was tested at the concentrations 0.1 microM, 1 microM and 10 microM. Tibolone reduced the synthesis of endothelin as well as the concentrations of E-selectin, PAI-1 and pro-MMP-1. The magnitude of the effects on these markers varied and was in the range of 11%-42%. Concerning smooth muscle cells, tibolone elicited no changes in the proliferation compared to control values. These data suggest that tibolone does have tumour cell-growth promoting effects in vitro. However, tibolone can positively influence the synthesis of markers in cell cultures of human female coronary artery, which modulate vascular tone and which play a decisive role in the various stages of atherosclerosis. Drawing a clinical consequence from our experiments would result in not recommending the use of tibolone in postmenopausal women at high risk for breast cancer development until long-term controlled clinical studies have been performed on the effect of tibolone administration and breast cancer risk. Experimental studies, such as the present one, are useful to explore mechanisms, but clearly cannot replace clinical studies.

Breast Neoplasms↗

PubMed2003

Effect of 2-methoxyestradiol on the growth of methyl-nitroso-urea (MNU)-induced rat mammary carcinoma.

The present study investigated the influence of the endogenous estradiol metabolite 2-methoxyestradiol (2ME) on the growth of methyl-nitroso-urea (MNU)-induced mammary carcinoma in the rat. 2ME was administered by means of subcutaneously implanted osmotic pumps for a period of 4 weeks. The dosages of 2ME were 1 and 5mg/kg per day, the control animals received saline. At the low dosage of 2ME a stimulation of tumor growth was observed, whereas at the high dosage an inhibition was found. The urinary excretion of 15 estradiol metabolites revealed that 2ME triggered strong changes in estrogen metabolism in the organism. Our data show that 2ME may elicit both stimulation and inhibition of tumor growth depending on the dosage used, a fact which should be considered in case of therapeutic use.

2-Methoxyestradiol↗