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Per Eystein Lonning - One of the best experts on this subject based on the ideXlab platform.
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phase iii randomized trial of Droloxifene and tamoxifen as first line endocrine treatment of er pgr positive advanced breast cancer
Breast Cancer Research and Treatment, 2002Co-Authors: Aman U Buzdar, Per Eystein Lonning, Kathleen I. Pritchard, Daniel F Hayes, A Elkhoudary, M Lichinitser, R Gopal, Geoffrey Falkson, Allan Lipton, K WolterAbstract:Purpose:This trial was designed to demonstrate equivalence between Droloxifene 40 mg/d and tamoxifen 20 mg/d as first-line treatment in pre- and post-menopausal women with ER+ and/or PgR+ advanced breast cancer based on time to disease progression and tumor response.
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influence of Droloxifene on metastatic breast cancer as first line endocrine treatment
Acta Oncologica, 1998Co-Authors: Helce Haarstad, Per Eystein Lonning, S Gundersen, Nils Kristian Raabe, Erik Wist, Stener KvinnslandAbstract:The effect of Droloxifene (3-hydroxytamoxifen) given as first-line endocrine treatment was evaluated in 39 postmenopausal women with advanced receptor-positive or receptor-unknown breast cancer. The patients had not received any previous anticancer therapy apart from adjuvant treatment. The overall response rate (CR + PR) was 51% (8% CR, 43% PR), 95% confidence interval + 15.7%. Median time to progression (all patients) was 8 months, the median time to response 2 months, while the median duration of response was 10 months. The drug was well tolerated with no major side effects recorded; 16% of the patients experienced hot flushes. The response to Droloxifene recorded in the present study is in accordance with the response rates to tamoxifen as first-line treatment in identical groups of patients.
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Insulin-Like Growth Factors in Breast Cancer
Acta Oncologica, 1996Co-Authors: S I Helle, Per Eystein LonningAbstract:insulin-like growth factor (IGF)-I is one of the most potent mitogens to many breast cancer cell lines in vitro. Effective growth inhibition in vitro may be achieved by antibodies to the type I IGF receptor (IGF-IR) or by using antisense strategies. Most human breast cancers express IGF-IR in vivo. Thus, different therapeutic strategies aimed at inhibiting ligand stimulation of the IGF-IR may be an attractive treatment option against breast cancer. Several drugs commonly used in breast cancer influence the IGF system both in vitro and in vivo. While antioestrogens such as tamoxifen and Droloxifene reduce the expression of IGF-IR in vitro and suppress plasma levels of IGF-I but elevate IGF-binding protein-1 in vivo, megestrol acetate may reduce the delivery of IGFs to the tissues by inhibition of IGFBP-3 protease activity.
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influence of Droloxifene on plasma levels of insulin like growth factor igf i pro igf iie insulin like growth factor binding protein igfbp 1 and igfbp 3 in breast cancer patients
The Journal of Steroid Biochemistry and Molecular Biology, 1996Co-Authors: S I Helle, M Tally, K Hall, Gun Anker, Per Eystein LonningAbstract:The influence of the novel anti-estrogen Droloxifene on the insulin-like growth factor (IGF) system in plasma was studied in two groups of breast cancer patients receiving Droloxifene 40 mg o.d. (group 1, n = 6) or 100 mg o.d. (group 2, n = 7). Fasting blood samples were obtained from all patients before treatment and after 3 months (group 1) or 6 months (group 2) on Droloxifene treatment, except for two patients in group 2 from whom the second sample was obtained following 2 months on treatment when the drug was to be terminated due to progressive disease. Insulin-like growth factor (IGF)-I, insulin-like growth factor binding protein (IGFBP)-1, IGFBP-3 and pro-IGF-IIE (IGF-IIE) were measured by radioimmunoassay. In patients in group 1, plasma IGF-I levels decreased by a mean value of 20% (P 0.1). In group 2 we observed a 42% decrease in IGF-I during treatment (P < 0.025), while the level of IGFBP-1 increased by a mean value of 70% (P < 0.025). No significant effect on IGF-IIE or IGFBP-3 was noted in any of the groups. The change in plasma IGF-I and IGFBP-1 observed during treatment with Droloxifene resembles what is found in patients treated with tamoxifen. As IGF-I is a potent mitogen for breast cancer cells in vitro, a decrease in the plasma level of this growth factor with an increase in the concentration of IGFBP-1 may contribute to the anti-tumour effects of Droloxifene.
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influence of Droloxifene 3 hydroxytamoxifen 40 mg daily on plasma gonadotrophins sex hormone binding globulin and estrogen levels in postmenopausal breast cancer patients
The Journal of Steroid Biochemistry and Molecular Biology, 1995Co-Authors: Jurgen Geisler, Dagfinn Ekse, S Hosch, Per Eystein LonningAbstract:Droloxifene (3-hydroxytamoxi fen) is a novel antiestrogen currently undergoing clinical investigations for treatment of breast cancer patients. We measured plasma levels of sex hormone binding globulin (SHBG) and the gonadotrophins (LH and FSH) at baseline and after 3 months on treatment in a group of fourteen postmenopausal women treated with Droloxifene 40 mg daily. Plasma levels of estrone (El), estradiol (E2) and estrone sulphate (EIS) were measured in a subgroup of eight patients. Plasma SHBG increased during treatment with Droloxifene by a mean value of 16.6% (P < 0.05), while plasma levels of LH and FSH decreased by a mean value of 15.7% (n.s.) and 18.1% (P < 0.05), respectively. Plasma levels of E2 and E1 fell slightly (mean decrease 19.4 and 16.7% respectively, n.s.). On the contrary, plasma levels of EIS increased by a mean value of 23.5% (P = 0.068). The ratio of E~S to E1 and E1S to E2 increased by a mean value of 48.3% (P < 0.025) and 53.2% (P < 0.025), respectively. The effect of Droloxifene 40 mg daily on plasma levels of SHBG resembles what is seen during treatment with tamoxifen but occurs to a smaller extent. Contrary to tamoxifen, Droloxifene caused a minor suppression of plasma LH levels, suggesting Droloxifene to have less estrogen agonistic effects on the pituitary.
H. J. Staab - One of the best experts on this subject based on the ideXlab platform.
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Investigations of Droloxifene and other hormone manipulations onN-nitrosomethylurea-induced rat mammary tumours
Journal of Cancer Research and Clinical Oncology, 1992Co-Authors: G. Winterfeld, P. Hauff, M. Görlich, W. Arnold, I. Fichtner, H. J. StaabAbstract:The effect of Droloxifene, a new anti-oestrogenic drug, on N -nitrosomethylurea-induced mammary tumours of Sprague-Dawley rats was investigated and compared with that of tamoxifen. The response of tumour growth to ovariectomy or to treatment with aminoglutethimide or high doses of oestradiol was also studied. Ovariectomy was by far the most effective treatment for mammary-tumour-bearing animals. More than 75% of the tumours in ovariectomized rats did not grow progressively but remained in remission for up to 12 weeks after castration when the experiment was terminated. The inhibitory effects of Droloxifene and tamoxifen on mammary tumour growth were similar, but body weight loss of animals treated with tamoxifen was more marked than that of animals treated with Droloxifene at the same dose and schedule.
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Investigations of Droloxifene and other hormonal manipulations onN-nitrosomethylurea-induced rat mammary tumours
Journal of Cancer Research and Clinical Oncology, 1992Co-Authors: M. Görlich, G. Winterfeld, P. Hauff, W. Arnold, I. Fichtner, H. J. StaabAbstract:In N -nitrosomethylurea-induced rat mammary tumours, tamoxifen is found to compete at the binding sites of the oestradiol receptor if a receptor determination is performed 1 day following the last drug application to animals. Despite a higher binding affinity of Droloxifene (3-OH-tamoxifen) to oestradiol receptor, compared to tamoxifen, its influence on the measurable receptor quantity is only very weak or not demonstrable. Therefore, binding affinity is not a valid explanation for the different influences of the two anti-oestrogens on the receptor. These only can be attributed to different behaviour patterns of both substances in relation to their half-lives and metabolism and accumulation in the organism. Owing to the short half-life of Droloxifene, even 1 day after the last application too little drug is available to compete for oestradiol binding sites. In the case of both anti-oestrogenic substances, cessation of drug application for 8 weeks abolished any influence on the oestradiol receptor. Furthermore, failure of aminoglutethimide to influence the oestradiol receptor could be observed because this substance does not act via this receptor. The experiments performed confirm literature data regarding the effect of aminoglutethimide therapy on oestradiol receptors breast tumour tissue of human beings. In summary: receptor investigations of N -nitrosomethylurea-induced rat mammary tumours, used as a model to test therapy regimens with Droloxifene or other drugs with a short half-life, may be of limited value only.
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investigations of Droloxifene and other hormonal manipulations on n nitrosomethylurea induced rat mammary tumours 2 influence on oestrogen receptor
Journal of Cancer Research and Clinical Oncology, 1992Co-Authors: M. Görlich, G. Winterfeld, P. Hauff, W. Arnold, I. Fichtner, H. J. StaabAbstract:In N-nitrosomethylurea-induced rat mammary tumours, tamoxifen is found to compete at the binding sites of the oestradiol receptor if a receptor determination is performed 1 day following the last drug application to animals. Despite a higher binding affinity of Droloxifene (3-OH-tamoxifen) to oestradiol receptor, compared to tamoxifen, its influence on the measurable receptor quantity is only very weak or not demonstrable. Therefore, binding affinity is not a valid explanation for the different influences of the two anti-oestrogens on the receptor
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investigations of Droloxifene and other hormone manipulations on n nitrosomethylurea induced rat mammary tumours 1 influence on tumour growth
Journal of Cancer Research and Clinical Oncology, 1992Co-Authors: G. Winterfeld, P. Hauff, M. Görlich, W. Arnold, I. Fichtner, H. J. StaabAbstract:The effect of Droloxifene, a new anti-oestrogenic drug, onN-nitrosomethylurea-induced mammary tumours of Sprague-Dawley rats was investigated and compared with that of tamoxifen. The response of tumour growth to ovariectomy or to treatment with aminoglutethimide or high doses of oestradiol was also studied. Ovariectomy was by far the most effective treatment for mammary-tumour-bearing animals. More than 75% of the tumours in ovariectomized rats did not grow progressively but remained in remission for up to 12 weeks after castration when the experiment was terminated. The inhibitory effects of Droloxifene and tamoxifen on mammary tumour growth were similar, but body weight loss of animals treated with tamoxifen was more marked than that of animals treated with Droloxifene at the same dose and schedule.
David D. Thompson - One of the best experts on this subject based on the ideXlab platform.
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estrogen induced genes in the uterus of ovariectomized rats and their regulation by Droloxifene and tamoxifen
The Journal of Steroid Biochemistry and Molecular Biology, 1998Co-Authors: Ramon Riveragonzalez, David D. Thompson, Donna N Petersen, George T Tkalcevic, Thomas A BrownAbstract:Abstract The identification and characterization of estrogen regulated genes in reproductive tissues is an important step in understanding estrogen's mechanism of action in sexual development and neoplasia. It is also important, given the clinical interest, to evaluate the molecular effects of estrogen agonists/antagonists such as tamoxifen and Droloxifene in reproductive tissues. In this report, our goal was to identify estrogen regulated genes in the uterus and to compare the regulation by estrogen and tamoxifen with that of Droloxifene. A subtractive cDNA library strategy was developed to identify estrogen-regulated genes in the uteri of ovariectomized rats 4 h after treatment with 17- α -ethynyl estradiol (30 μ g/kg). The mRNAs encoding 8 genes were confirmed by Northern blot analysis to be induced at early times following estrogen administration. Calcium binding protein 9 kDa and complement protein 3 are well characterized estrogen regulated genes that were identified in the library and served as markers for estrogen action. In addition, mRNAs encoding the interleukin 4 receptor, heat-shock protein 70 kDa, metallothionein, tumor necrosis factor regulated gene 6, inositol-1-monophosphate synthase, and cyr-61 were induced in the uterus by estrogen. The identified mRNAs were then examined for regulation by Droloxifene (1 and 10 mg/kg, p.o.) and tamoxifen (10 mg/kg, p.o.). Both Droloxifene and tamoxifen induced mRNA levels for all of these genes. However, clear quantitative and temporal differences were observed when comparing estrogen versus Droloxifene versus tamoxifen. For example, estrogen induced IL4 receptor mRNA to a greater degree than did tamoxifen or Droloxifene. Conversely, tamoxifen resulted in a much greater induction of cyr61 than did either estrogen or Droloxifene. Droloxifene at 1 mg/kg, an efficacious dose for prevention of bone loss in this model, did not or only slightly induced the mRNA for all of the genes examined with the exception of cyr61. In conclusion, the modified subtractive library method used in this study proved to be efficient in the identification of estrogen-regulated genes in the uterus. The identities of the regulated genes were consistent with the concept that estrogen functions to prime uterine tissue for increased responsivity to extracellular signals such as growth factors and cytokines. Elucidating the physiological role of these newly identified estrogen responsive genes and the mechanisms responsible for the different responses to Droloxifene versus estrogen and tamoxifen may be important in enhancing our understanding of tissue selective estrogen agonists/antagonists.
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common mechanism for the estrogen agonist and antagonist activities of Droloxifene
Journal of Cellular Biochemistry, 1997Co-Authors: William A Grasser, David D. Thompson, Vishwas M ParalkarAbstract:The incidence of postmenopausal osteoporosis is increasing as the population ages. Even though estrogen replacement therapy has proven beneficial in reducing the number of skeletal fractures, the known risks and associated side-effects of estrogen replacement therapy make compliance poor. Recent research has focused on the development of tissue specific estrogen agonist/anatagonists such as Droloxifene which can prevent estrogen deficiency-induced bone loss without causing uterine hypertrophy. Furthermore, Droloxifene acts as a full estrogen antagonist on breast tissue and is being evaluated for treatment of advanced breast cancer. In this report we propose a common mechanism of action for Droloxifene that underlies its estrogen agonist and antagonist effects in different tissues. Droloxifene and estrogen, which have identical effects on bone in vivo, both induced p53 expression and apoptosis in cells of in vitro rat bone marrow cultures resulting in a decrease in the number of bone-resorbing osteoclasts. Droloxifene is growth inhibitory in MCF-7 human breast cancer cells and therefore acts as an antagonist, whereas estrogen is mitogenic to these cells and acts as an agonist. Droloxifene, but not estrogen, induced p53 expression and apoptosis in MCF-7 cells. These results indicate that the induction of apoptosis by Droloxifene may be the common mechanism for both its estrogen agonist effects in bone and its antagonist effects in breast tissue. J. Cell. Biochem. 65:159–171. © 1997 Wiley-Liss, Inc.
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Droloxifene inhibits cortical bone turnover associated with estrogen deficiency in rats
Bone, 1995Co-Authors: H K Chen, Hollis A. Simmons, Christine M. Pirie, D. Todd Crawford, Hua Zhu Ke, Y F, H Qi, David D. ThompsonAbstract:Abstract Droloxifene (DRO), an estrogen antagonist/agonist, has been shown to possess estrogen-like effects in inhibiting bone turnover leading to cancellous bone loss in ovariectomized (OVX) rats. The purpose of this study was to determine the effects of DRO on cortical bone turnover in OVX rats. Sprague-Dawley female rats at 5 months of age were sham-operated (sham, n=8) and orally treated with vehicle, or OVX (n=56) and orally treated with either vehicle, DRO at 0.1, 1, 5, or 10 mg/kg/day, or 17α-ethynyl estradiol (EE) at 3 or 30 μg/kg/day for 4 weeks. Static and dynamic cortical bone histomorphometry was performed on double fluorescent labeled, undecalcified cross sections of tibial diaphyses (proximal to the tibiofibular junction). There were no significant differences in tibial diaphyseal cross sectional area, marrow cavity area, and cortical bone area between groups after 4 weeks of administration. Periosteal mineralizing surface, mineral apposition rate, and bone formation rate-surface referent and endocortical eroded surface increased significantly, while endocortical mineral apposition rate and bone formation rate-surface referent increased nonsignificantly in OVX controls compared to sham controls. Treatment with DRO at doses of 0.1 to 10 mg/kg/day dose-dependently attenuated the OVX-induced higher bone formation indices in both the periosteal and endocortical surfaces and higher bone resorption index in the endocortical surface. At the highest dose (10 mg/kg/day), DRO completely inhibited the increases in bone formation and resorption indices in OVX rats. Similarly, EE at 30 μg/kg/day inhibited the increase in periosteal and endocorrical bone formation and endocortical bone resorption associated with estrogen deficiency in rats, while 3 μg/kg/day, EE decreased only periosteal mineral apposition rate in OVX rats. Our results indicated that DRO prevented OVX-induced higher bone turnover on endocortical surfaces and higher bone formation in periosteal surfaces of tibial diaphyses in an identical manner to EE. Therefore, we concluded that DRO is an estrogen agonist on cortical bone in ovariectomized rats.
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Droloxifene a new estrogen antagonist agonist prevents bone loss in ovariectomized rats
Endocrinology, 1995Co-Authors: Hua Zhu Ke, Hollis A. Simmons, Christine M. Pirie, D. Todd Crawford, David D. ThompsonAbstract:The purpose of this study was to determine the effects of Droloxifene (DRO), a new estrogen antagonist/agonist, on bone turnover, bone mass, total serum cholesterol, and uterine weight in rats made estrogen deficient by ovariectomy. Sprague-Dawley female rats were ovariectomized (OVX) or sham operated (sham) at 5 months of age and treated with 17 beta-estradiol (E2) at 30 micrograms/kg, sc, daily or with DRO at 5, 10, or 20 mg/kg.day, orally, for 4 weeks. At the time of death, body weight gain, uterine weight, and total serum cholesterol were measured. Bone area, bone mineral content (BMC), and bone mineral density (BMD) of whole femora, distal femoral metaphyses, femoral shaft, and proximal femora were determined ex vivo using dual energy x-ray absorptiometry. Static and dynamic cancellous bone histomorphometric analysis of proximal tibial metaphyses was performed in double fluorescent labeled, undecalcified, 4- and 10-microns longitudinal sections. Body weight gain in E2-treated OVX rats was significant...
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Droloxifene, a new estrogen antagonist/agonist, prevents bone loss in ovariectomized rats.
Endocrinology, 1995Co-Authors: Hua Zhu Ke, Hollis A. Simmons, Christine M. Pirie, D. Todd Crawford, David D. ThompsonAbstract:The purpose of this study was to determine the effects of Droloxifene (DRO), a new estrogen antagonist/agonist, on bone turnover, bone mass, total serum cholesterol, and uterine weight in rats made estrogen deficient by ovariectomy. Sprague-Dawley female rats were ovariectomized (OVX) or sham operated (sham) at 5 months of age and treated with 17 beta-estradiol (E2) at 30 micrograms/kg, sc, daily or with DRO at 5, 10, or 20 mg/kg.day, orally, for 4 weeks. At the time of death, body weight gain, uterine weight, and total serum cholesterol were measured. Bone area, bone mineral content (BMC), and bone mineral density (BMD) of whole femora, distal femoral metaphyses, femoral shaft, and proximal femora were determined ex vivo using dual energy x-ray absorptiometry. Static and dynamic cancellous bone histomorphometric analysis of proximal tibial metaphyses was performed in double fluorescent labeled, undecalcified, 4- and 10-microns longitudinal sections. Body weight gain in E2-treated OVX rats was significant...
Zhiping Gu - One of the best experts on this subject based on the ideXlab platform.
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apoptosis induced by Droloxifene and c myc bax bcl 2 protein expression in corpus luteum of pregnant rats
Acta Pharmacologica Sinica, 2016Co-Authors: Ying Leng, Zhiping GuAbstract:Aim: To investigate the effects of Droloxifene on apoptosis of luteal cells in pregnant rats, and analyze the possible relationships between the expression of C-myc, Bax, Bcl-2 protein in corpus luteum and apoptosis of luteal cells induced by Droloxifene. Methods: Pregnant rats were treated orally with Droloxifene 20 mg . kg-1 on d 2. Ovaries were collected on d 4 or d 8 for detecting the apoptosis of luteal cells by hematoxylin-eosin staining and terminal deoxyribonucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labelling (TUNEL), and observing the expression of C-myc, Bax, Bcl-2 protein in corpus luteum by immunohistochemistry. The ovarian fresh weight, protein contents, and serum progesterone levels were also determined on d 4 and d 8. Results: Apoptotic luteal cells appeared on d 4 and more apoptotic cells could be observed on d 8 in Droloxifene treated rats. The ovarian fresh weight, protein contents, and serum progesterone concentration were found to be decreased significantly on d 8 as compared to the control group. In corpus luteum of Droloxifene treated rats, the increased expression of C-myc and Bax protein could be observed on d 4 and d 8, respectively, whereas no obvious changes could be found in the expression of Bcl-2 protein. Conclusion: Droloxifene could induce apoptosis of luteal cells of preimplantation in pregnant rats. An increased expression of C-myc protein and Bax/Bcl-2 ratio could be induced by Droloxifene, which might be associated with the mechanisms of apoptosis of luteal cells induced by Droloxifene.
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effects of Droloxifene on apoptosis and bax bcl 2 protein expression of luteal cells in pseudopregnant rats
Acta Pharmacologica Sinica, 2001Co-Authors: Ying Leng, Ying Feng, Zhiping GuAbstract:Aim: To study the effects of Droloxifene on apoptosis and the expression of Bax and Bcl-2 protein in corpus luteum of pseudopregnant rats. Methods: HE staining was used to examine the histological changes of ovaries. Apoptosis detection in situ was performed with TUNEL method. Expression of Bax and Bcl-2 protein was observed by immunohistochemistry analysis. Results: Apoptosis of luteal cells during the spontaneous regression of corpus luteum of pseudopregnant rats appeared on d 13 of pseudopregnancy, and the marked increase of apoptotic luteal cells could be observed on d 15. When pseudopregnant rats were treated with Droloxifene 20 mg . Kg on d 2, apoptosis of luteal cells could be observed on d 8 and the duration of pseudopregnancy could be shortened from (15.5 +\- 1.1) d to (12.8 +\- 1.6) d. In pseudopregnant rats, the expression of Bax and Bcl-2 protein was found in the cytoplasm of luteal cells. However, no obvious differences in the intensity or localization could be found during various days of the pseudopregnancy, while an increase in Bax and a decrease in Bcl-2 protein expression could be induced by Droloxifene treatment. Conclusion: Droloxifene could facilitate apoptosis of luteal cells in pseudopregnant rats and shorten the period of pseudopregnancy. An increased Bax/Bcl-2 ratio might be involved in the facilitation of apoptosis induced by Droloxifene in corpus luteum of pseudopregnant rats.
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apoptosis induced by Droloxifene and c myc bax and bcl 2 mrna expression in cultured luteal cells of rats
European Journal of Pharmacology, 2000Co-Authors: Ying Leng, Zhiping GuAbstract:Abstract Droloxifene is a tamoxifen derivative whose effects in the therapy of human breast cancer and postmenopausal osteoporosis have been studied widely. We had found that Droloxifene could induce apoptosis of luteal cells of rat in vitro, but its mechanisms were unknown. In the present study, the expression of c-myc, bax and bcl-2 mRNA in cultured rat luteal cells during apoptosis induced by Droloxifene was investigated and possible associations between these genes and apoptosis were analyzed. Cultured luteal cells of rats were incubated with Droloxifene at various concentrations and with treatment durations. Occurrence of apoptosis was detected by terminal deoxyribonucleotidyl tranferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL), DNA staining and DNA electrophoresis. Expression of these genes' mRNA was determined by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). The results showed that the c-myc and bax mRNA levels increased as concentrations or treatment durations of Droloxifene increased, while the bcl-2 mRNA level exhibited no changes. A marked increase of c-myc and bax mRNA appeared respectively with 12 and 24 h of treatment, while a clear increase of apoptosis of luteal cells was found at 18 h. These results suggested that Droloxifene could induce apoptosis of luteal cells of rat in vitro. The increase of c-myc mRNA expression might be one of the initiating factors and the elevated ratio of bax/bcl-2 mRNA was also probably involved in this effect.
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effects of anordrin Droloxifene nomegestrol and mifepristone on cultured rat luteal cell apoptosis
Acta Pharmacologica Sinica, 1999Co-Authors: Ying Leng, Bo Yang, Zhiping GuAbstract:AIM: To study the effect of four kinds of antifertility agents anordrin(Ano), Droloxifene(Dro), nomegestrol (Nom), and mifepristone (Mif) on luteal cell apoptosis. METHODS: Cultured rat luteal cells were incubated with different agents. HE stain was used to observe morphological changes. Extracted DNA was electrophoresed on agarose gel. Apoptotic cells were quantitated by flow cytometry. RESULTS: All 4 drugs reduced cell viability. Dro induced apoptosis while the other 3 drugs induced necrosis. Typical DNA ladders were observed after cells were incubated with Dro and there were 15.4%, 75.4%, or 90.5% apoptotic cells after treatment with Dro 1.25, 2.5, or 3.75 mg.L-1, respectively. CONCLUSION: Dro induced apoptosis while Ano, Nom, and Mif induced necrosis in cultured rat luteal cells.
Ying Leng - One of the best experts on this subject based on the ideXlab platform.
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apoptosis induced by Droloxifene and c myc bax bcl 2 protein expression in corpus luteum of pregnant rats
Acta Pharmacologica Sinica, 2016Co-Authors: Ying Leng, Zhiping GuAbstract:Aim: To investigate the effects of Droloxifene on apoptosis of luteal cells in pregnant rats, and analyze the possible relationships between the expression of C-myc, Bax, Bcl-2 protein in corpus luteum and apoptosis of luteal cells induced by Droloxifene. Methods: Pregnant rats were treated orally with Droloxifene 20 mg . kg-1 on d 2. Ovaries were collected on d 4 or d 8 for detecting the apoptosis of luteal cells by hematoxylin-eosin staining and terminal deoxyribonucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labelling (TUNEL), and observing the expression of C-myc, Bax, Bcl-2 protein in corpus luteum by immunohistochemistry. The ovarian fresh weight, protein contents, and serum progesterone levels were also determined on d 4 and d 8. Results: Apoptotic luteal cells appeared on d 4 and more apoptotic cells could be observed on d 8 in Droloxifene treated rats. The ovarian fresh weight, protein contents, and serum progesterone concentration were found to be decreased significantly on d 8 as compared to the control group. In corpus luteum of Droloxifene treated rats, the increased expression of C-myc and Bax protein could be observed on d 4 and d 8, respectively, whereas no obvious changes could be found in the expression of Bcl-2 protein. Conclusion: Droloxifene could induce apoptosis of luteal cells of preimplantation in pregnant rats. An increased expression of C-myc protein and Bax/Bcl-2 ratio could be induced by Droloxifene, which might be associated with the mechanisms of apoptosis of luteal cells induced by Droloxifene.
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anti implantation effect of Droloxifene in rats and its relationship with anti estrogenic activity
Acta Pharmacologica Sinica, 2005Co-Authors: Yong Huang, Ying Feng, Yu Shen, Ying LengAbstract:Anti-implantation effect of Droloxifene in rats and its relationship with anti-estrogenic activity
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effects of Droloxifene on apoptosis and bax bcl 2 protein expression of luteal cells in pseudopregnant rats
Acta Pharmacologica Sinica, 2001Co-Authors: Ying Leng, Ying Feng, Zhiping GuAbstract:Aim: To study the effects of Droloxifene on apoptosis and the expression of Bax and Bcl-2 protein in corpus luteum of pseudopregnant rats. Methods: HE staining was used to examine the histological changes of ovaries. Apoptosis detection in situ was performed with TUNEL method. Expression of Bax and Bcl-2 protein was observed by immunohistochemistry analysis. Results: Apoptosis of luteal cells during the spontaneous regression of corpus luteum of pseudopregnant rats appeared on d 13 of pseudopregnancy, and the marked increase of apoptotic luteal cells could be observed on d 15. When pseudopregnant rats were treated with Droloxifene 20 mg . Kg on d 2, apoptosis of luteal cells could be observed on d 8 and the duration of pseudopregnancy could be shortened from (15.5 +\- 1.1) d to (12.8 +\- 1.6) d. In pseudopregnant rats, the expression of Bax and Bcl-2 protein was found in the cytoplasm of luteal cells. However, no obvious differences in the intensity or localization could be found during various days of the pseudopregnancy, while an increase in Bax and a decrease in Bcl-2 protein expression could be induced by Droloxifene treatment. Conclusion: Droloxifene could facilitate apoptosis of luteal cells in pseudopregnant rats and shorten the period of pseudopregnancy. An increased Bax/Bcl-2 ratio might be involved in the facilitation of apoptosis induced by Droloxifene in corpus luteum of pseudopregnant rats.
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apoptosis induced by Droloxifene and c myc bax and bcl 2 mrna expression in cultured luteal cells of rats
European Journal of Pharmacology, 2000Co-Authors: Ying Leng, Zhiping GuAbstract:Abstract Droloxifene is a tamoxifen derivative whose effects in the therapy of human breast cancer and postmenopausal osteoporosis have been studied widely. We had found that Droloxifene could induce apoptosis of luteal cells of rat in vitro, but its mechanisms were unknown. In the present study, the expression of c-myc, bax and bcl-2 mRNA in cultured rat luteal cells during apoptosis induced by Droloxifene was investigated and possible associations between these genes and apoptosis were analyzed. Cultured luteal cells of rats were incubated with Droloxifene at various concentrations and with treatment durations. Occurrence of apoptosis was detected by terminal deoxyribonucleotidyl tranferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL), DNA staining and DNA electrophoresis. Expression of these genes' mRNA was determined by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). The results showed that the c-myc and bax mRNA levels increased as concentrations or treatment durations of Droloxifene increased, while the bcl-2 mRNA level exhibited no changes. A marked increase of c-myc and bax mRNA appeared respectively with 12 and 24 h of treatment, while a clear increase of apoptosis of luteal cells was found at 18 h. These results suggested that Droloxifene could induce apoptosis of luteal cells of rat in vitro. The increase of c-myc mRNA expression might be one of the initiating factors and the elevated ratio of bax/bcl-2 mRNA was also probably involved in this effect.
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effects of anordrin Droloxifene nomegestrol and mifepristone on cultured rat luteal cell apoptosis
Acta Pharmacologica Sinica, 1999Co-Authors: Ying Leng, Bo Yang, Zhiping GuAbstract:AIM: To study the effect of four kinds of antifertility agents anordrin(Ano), Droloxifene(Dro), nomegestrol (Nom), and mifepristone (Mif) on luteal cell apoptosis. METHODS: Cultured rat luteal cells were incubated with different agents. HE stain was used to observe morphological changes. Extracted DNA was electrophoresed on agarose gel. Apoptotic cells were quantitated by flow cytometry. RESULTS: All 4 drugs reduced cell viability. Dro induced apoptosis while the other 3 drugs induced necrosis. Typical DNA ladders were observed after cells were incubated with Dro and there were 15.4%, 75.4%, or 90.5% apoptotic cells after treatment with Dro 1.25, 2.5, or 3.75 mg.L-1, respectively. CONCLUSION: Dro induced apoptosis while Ano, Nom, and Mif induced necrosis in cultured rat luteal cells.
