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  • 1
    Keywords: Medicine ; Oncology ; Toxicology ; Endocrinology ; Biomedicine ; Cancer Research ; Pharmacology/Toxicology ; Oncology ; Endocrinology ; Springer eBooks
    Description / Table of Contents: Discovery and Pharmacology of Nonsteroidal Estrogens and Antiestrogens -- Tamoxifen Goes Forward Alone -- Metabolites of Tamoxifen as the Basis of Drug Development -- Adjuvant Therapy – The Breakthrough -- The Wisconsin Story in the 1980’s: Discovery of Target Site Specific Estrogen Action -- Carcinogenesis and Tamoxifen -- Chemoprevention: Cinderella waiting for the ball -- Tamoxifen and Raloxifene head to head: The STAR TRIAL -- Acquired resistance to Tamoxifen: back to the beginning -- The legacy of Tamoxifen -- Appendix: Four decades of discovery in breast cancer research and treatment – an interview with V. Craig Jordan by Marc Poirot -- Selected Awards that Recognize the Contribution of Tamoxifen and Raloxifene to Medicine
    Abstract: Tamoxifen is a pioneering medicine for the treatment and prevention of breast cancer. It is the first drug targeted therapy in cancer to be successful. Tamoxifen targets the tumor estrogen receptor. The therapy is known to have saved the lives of millions of women over the past 40 years. This monograph, written by V. Craig Jordan - known as the “father of tamoxifen” - and his Tamoxifen Team at the Georgetown University Washington DC, illustrates the journey of this milestone in medicine. It includes a personal interview with V. Craig Jordan about his four decades of discovery in breast cancer research and treatment. V. Craig Jordan was there for the birth of tamoxifen as he is credited for reinventing a “failed morning after contraceptive” to become the “gold standard” for the treatment of breast cancer. He contributed to every aspect of tamoxifen application in therapeutics and all aspects of tamoxifen’s pharmacology. He discovered the selective estrogen receptor modulators (SERMs) and explored the new biology of estrogen-induced apoptosis
    Pages: XXII, 199 p. 54 illus., 32 illus. in color. : online resource.
    ISBN: 9783034806640
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1573-7217
    Keywords: antiestrogen ; adjuvant therapy ; ICI 46,474 ; endocrine therapy ; tamoxifen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Tamoxifen, a nonsteroidal antiestrogen, is now the endocrine treatment most widely used in breast cancer, both in the adjuvant and advanced disease settings. Here we will trace the development of tamoxifen for advanced breast cancer in postmenopausal patients, consider the biological basis for the recent successful use of tamoxifen for long-term adjuvant therapy, and discuss the use of tamoxifen in premenopausal patients with advanced disease. In part, this will be a historical review offered as a tribute to the late Dr. Arthur L. Walpole, who must receive the chief credit for the discovery of tamoxifen and its subsequent application as an anticancer agent.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1573-7217
    Keywords: antiestrogen ; athymic mice ; drug metabolism ; DMBA-induced tumors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Toremifene is a nonsteroidal antiestrogen currently being evaluated for the treatment of breast cancer. Toremifene (10−10-10−6 M) inhibited the growth of MCF-7 breast cancer cellsin vitro but was ineffective against hormone-independent MDA-MB-231 cells. This activity was reproducedin vivo using the athymic mouse model. Maximal MCF-7 tumor growth was produced in athymic mice by circulating estradiol levels of approximately 200 pg/ml (from a 0.5 cm silastic capsule implanted sc). Toremifene (77 ± 44 µg/day from a 2 cm silastic capsule) inhibited estradiol (0.5 cm capsule)-stimulated growth by more than 70%. No tumor growth was observed in mice treated with toremifene alone, although toremifene acted as a weak partial agonist and potent antagonist on the mouse uterus. The growth of MDA-MB-231 tumors was not influenced by either estradiol or toremifene. Toremifene (200 µg/day) was effective in preventing the development of 7,12-dimethylbenzanthracene-induced rat mammary tumors when given po from day 28 after carcinogen administration. The antitumor activity was reversed if the toremifene was stopped. These findings indicate toremifene is a tumoristatic agent rather than a tumoricidal agent. Clinical trials with toremifene should employ an indefinite treatment strategy to control tumor recurrence in adjuvant studies.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1573-7217
    Keywords: antiestrogens ; estrogen receptor ; monohydroxytamoxifen ; pharmacology of tamoxifen ; tamoxifen metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Over the past decade, the non-steroidal antiestrogen tamoxifen has gained general acceptance for the palliative treatment of breast cancer. Although there has been much interest in the pharmacology of tamoxifen, our knowledge of its metabolism in laboratory animals and patients is incomplete and the precise mechanism of action within target tissue and breast tumor cells is unknown. This review briefly describes the pharmacology of tamoxifen in various laboratory species and patients. Several metabolites of tamoxifen are known and their relative potencies as estrogens and antiestrogens are compared with the parent compound. Apart from monohydroxytamoxifen, none of tamoxifen's metabolites are more potent antiestrogens, but a metabolite in the dog, Metabolite E, is fully estrogenic. Routine assays (tlc, HPLC, glc/ms) are available to detect tamoxifen, N-desmethyltamoxifen, monohydroxytamoxifen, and a newly identified metabolite, designated Metabolite Y, in biological fluids. Continuous therapy with tamoxifen (10 mg bid) produces steady-state levels (100–200 ng/ml serum) within 4 weeks. Levels of N-desmethyltamoxifen are often up to twice the levels achieved with tamoxifen, while levels of monohydroxytamoxifen and Metabolite Y are below 10 ng/ml. Although monohydroxytamoxifen has a high binding affinity for the estrogen receptor, the metabolic activation of tamoxifen is an advantage rather than a requirement for antiestrogenic activity. The action of tamoxifen in vivo is the net result of the individual actions of the parent compound and its metabolites competing for the occupation of receptors within target tissues and tumors.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1573-7217
    Keywords: antiestrogens ; breast cancer ; tamoxifen ; drug resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Breast cancer is the most common malignancy occurring in Western women, and is one of the leading causes of cancer mortality. The nonsteroidal antiestrogen tamoxifen has been shown to be an effective treatment for pre and postmenopausal women with all stages of the disease. Tamoxifen provides effective palliation when used to treat patients with advanced disease, and adjuvant tamoxifen therapy produces significant increases in both disease-free and overall survival (Early Breast Cancer Trialists Collaborative Group. Lancet 339:1-15, 71-85, 1992). Data from the laboratory have shown that the primary action of tamoxifen is tumoristatic rather than tumoricidal, and long-term therapy is therefore recommended. Unfortunately, many patients experience disease progression while taking tamoxifen. Some tamoxifen resistant tumors may remain sensitive to alternative endocrine therapies, while others may become refractory to any hormonal manipulation. Many models have been developedin vitro andin vivo to study the progression of breast cancer growth from tamoxifen sensitive to tamoxifen resistant. We and others have used long-term estrogen deprivation and long-term tamoxifen exposure to develop cell lines and tumors capable of growth in the presence of clinically relevant tamoxifen concentrations. Recently our laboratory has also shown that mutations in the estrogen receptor can cause an antiestrogen-occupied receptor to behave as though it were occupied by an estrogen. Breast cancer is a highly heterogeneous disease and it is likely that the mechanisms which cause tamoxifen resistant growth are equally heterogeneous. Several of the models from our laboratory and others which may contribute to an understanding of this complex phenomenon are discussed here.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1573-7217
    Keywords: DMBA-induced rat mammary tumors ; estrogen receptors ; tamoxifen ; tamoxifen metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The general pharmacology of tamoxifen in animals and man is reviewed with particular reference to the longterm adjuvant therapy of node-positive breast cancer. Rats with dimethylbenzanthracene (DMBA)-induced mammary carcinomata have been used extensively as a laboratory model to study hormone-dependent cancer. The administration of a 30-day course of tamoxifen (50 µg daily) starting 5, 15, 30, or 50 days after DMBA caused a delay in tumor appearance and decrease in the cumulative number of tumors that were induced by 200 days. Similarly, the administration of increasing doses of tamoxifen (0.2, 3, 50, and 800 µg daily) between 30 and 60 days after DMBA produced a dose-related delay in tumor appearance and a decrease in the cumulative number of tumors at 200 days. Since the tumors that were induced after tamoxifen still responded to ovariectomy, tamoxifen appears to act as an inhibitor of the tumor cell cycle rather than as a tumoricidal agent in this model. This principle was exemplified by comparing a short course (30 day) with a continuous course (170 day) of tamoxifen initiated 30 days after DMBA. The short course of therapy only delayed tumor appearance whereas continuous therapy maintained 90% of the animals in a tumor-free state. These data strongly support the use of long-term (up to five-year) adjuvant therapy with tamoxifen in patients as a suppressive therapy for homone-sensitive metastases.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1573-7217
    Keywords: estrogen receptor ; tamoxifen ; prevention ; endometrial cancer ; raloxifene ; long-term adjuvant therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In 1973, McGuire and Chamness (In: O'Malley BW and Means AR (eds) Receptors for Reproductive Hormones, Plenum Press) summarized their work on the estrogen receptor in animal and human breast tumors, and in so doing described a target for therapeutic intervention. At that time there were no clinically useful antiestrogens, but the subsequent development of tamoxifen for breast cancer therapy has revolutionized the approach to treatment. Long-term adjuvant tamoxifen adjuvant therapy (i.e. greater than one year) has proven efficacy to enhance the survival of breast cancer patients. In addition, because there is an associated 40% decrease in contralateral breast cancer during adjuvant tamoxifen therapy and tamoxifen maintains bone density and reduces fatal myocardial infarction, clinical trials to test the worth of tamoxifen as a preventive for breast cancer in high risk women have started in the United States, United Kingdom, and Italy. Initial concerns that long-term tamoxifen causes endometrial cancer have been placed in perspective and analyzed by a review of the literature. Tamoxifen only doubles the normal risk of detecting endometrial cancer, (i.e. to 2 per 1,000 tamoxifen-treated women per year), and 80% of these cases are early stage, good prognosis disease. Annual gynecological examinations and education are essential to provide reassurance for patients. The success of tamoxifen has encouraged the development of new antiestrogens to exploit the estrogen receptor as a therapeutic target. Droloxifene and TAT-59 mimic the metabolite 4-hydroxytamoxifen in having a high affinity for the estrogen receptor (Jordan et al, J Endocrinol 75:305, 1977). These drugs appear to have a pharmacological profile similar to tamoxifen. In contrast, the new pure antiestrogens have a distinct mechanism of action and will be valuable either as a first line therapy for advanced breast cancer or as a second line endocrine therapy after the failure of long-term adjuvant tamoxifen therapy. Finally, a new strategy is being developed to exploit the target site specific action of antiestrogens. Raloxifene, an antiestrogen with high affinity for the estrogen receptor but only weak estrogenicity for the uterus, prevents rat mammary tumorigenesis and maintains bone density. The drug is to be evaluated as a treatment for osteoporosis, but may also prevent the development of breast and endometrial cancer in a broad group of treated subjects. The identification of the estrogen receptor as a target for therapeutic opportunities has proved to be extremely beneficial for the control of breast cancer and has the added potential to control osteoporosis and coronary heart disease in women.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1573-7217
    Keywords: adjuvant therapy ; chemohormonal therapy ; long-term treatment ; metabolites ; tamoxifen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary One hundred twenty-four disease-free postoperative women with ipsilateral-node-positive breast carcinoma were evaluated to assess the metabolic handling and clinical side effects of adjuvant tamoxifen for periods in excess of five years. The patients received postoperative combination chemotherapy for a median of 14 months. Thirty-eight patients received no tamoxifen. Tamoxifen 10 mgs bid was administered to 86 patients during the chemotherapy duration and has been continued in 43 of these patients for up to five years after termination of chemotherapy. Serum samples obtained in 7 patients at 3 to 4-month intervals during the first 5 years revealed that levels of tamoxifen, N-desmethyltamoxifen, and metabolite Y were generally constant throughout the period of drug administration. There was no difference in side effects observed after stopping chemotherapy between the group continuing tamoxifen and the groups stopping tamoxifen or never receiving the drug. Relapse-free survival was superior with increasing duration of exposure to tamoxifen, but this observation can only be considered preliminary due to the small number of patients involved and the study design. The clinical effects observed and the failure to demonstrate the development of a host-metabolic tolerance to tamoxifen provides a rational basis for developing a clinical trial to continue adjuvant tamoxifen therapy for periods in excess of four years after chemotherapy.
    Type of Medium: Electronic Resource
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