Evaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model

Jordan, V. Craig; Allen, K. E.

doi:10.1016/0014-2964(80)90156-5

Cited by 195 publications

(73 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, a strategic plan was developing to use tamoxifen in a broader range of patient populations. Laboratory studies conducted in the 1970's showed that tamoxifen blocked estrogen binding to the ER [15][16][17], should be used as a long-term adjuvant therapy to suppress tumor recurrence [18][19][20] and the drug also had potential as a chemopreventive agent [21,22].…”

Section: Tamoxifen the First Sermmentioning

confidence: 99%

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

2007

View full text Add to dashboard Cite

The metabolism of tamoxifen is being redefined in the light of several important pharmacological observations. Recent studies have identified 4-hydroxy N-desmethyl tamoxifen (endoxifen) as an important metabolite of tamoxifen necessary for antitumor actions. The metabolite is formed through the enzymatic product of CYP2D6 which also interacts with specific selective serotonin reuptake inhibitors (SSRIs) used to prevent the hot flashes observed in up to 45% of patients taking tamoxifen. Additionally, the finding that enzyme variants of CYP2D6 do not promote the metabolism of tamoxifen to endoxifen means that significant numbers of women might not receive optimal benefit from tamoxifen treatment. Clearly these are particularly important issues not only for breast cancer treatment but also for selecting premenopausal women, at high risk for breast cancer, as candidates for chemoprevention using tamoxifen.

show abstract

Section: Tamoxifen the First Sermmentioning

confidence: 99%

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

2007

View full text Add to dashboard Cite

show abstract

“…ovariectomy, are essential to control tumour growth." (3) This notion lead to the idea that longer was going to be better as a strategy to employ for adjuvant tamoxifen therapy and provided a scientific foundation for the successful use of subsequent oestrogen deprivation, i.e. an aromatase inhibitor following 5 years of tamoxifen treatment (65,66).…”

Section: Foundationsmentioning

confidence: 99%

“…Clearly, there was a link between dose and anticancer action, but it was because higher doses were cleared from the body more slowly and not that the higher dose was more active. Tamoxifen was acting as a tumouristatic agent -the drug was effective as long as the drug was present to suppress tumour (Figure 2) (3,63,64 "(3) This notion lead to the idea that longer was going to be better as a strategy to employ for adjuvant tamoxifen therapy and provided a scientific foundation for the successful use of subsequent oestrogen deprivation, i.e. an aromatase inhibitor following 5 years of tamoxifen treatment (65,66).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Tamoxifen: Catalyst for the change to targeted therapy

Jordan

2008

European Journal of Cancer

178

131

View full text Add to dashboard Cite

In the early 1970's, a failed postcoital contraceptive, ICI 46,474, was reinvented as tamoxifen, the first targeted therapy for breast cancer. A cluster of papers published in the European Journal of Cancer described the idea of targeting tamoxifen to patients with oestrogen receptor positive tumours, and proposed the strategic value of using long-term tamoxifen therapy in an adjuvant setting with a consideration of the antitumour properties of the hydroxylated metabolites of tamoxifen. At the time, these laboratory results were slow to be embraced by the clinical community. Today, it is estimated that hundreds of thousands of breast cancer patients are alive today because of targeted long-term adjuvant tamoxifen therapy. Additionally, the first laboratory studies for the use of tamoxifen as a chemopreventive were published. Eventually, the worth of tamoxifen was tested as a chemopreventive and the drug is now known to have an excellent risk benefit ratio in high risk premenopausal women. Overall, the rigorous investigation of the pharmacology of tamoxifen facilitated tamoxifen's ubiquitous use for the targeted treatment of breast cancer, chemoprevention and pioneered the exploration of selective estrogen receptor modulators (SERMs). This new concept subsequently heralded the development of raloxifene, a failed breast cancer drug, for the prevention of osteoporosis and breast cancer without the troublesome side effect of endometrial cancer noted in postmenopausal women who take tamoxifen. Currently, the pharmaceutical industry is exploiting the SERM concept for all members of the nuclear receptor superfamily so that medicines can now be developed for diseases once thought impossible.A new dynasty gives dominion over the ruling dynasty through perseverance and not by sudden action (Ibn Khaldun 14 th Century Arab Historian) -and so it is with changes in the approach to cancer therapy. This article will focus specifically on a cluster of scientific papers (1-3) published in the European Journal of Cancer that presaged the dramatic changes that have occurred in the past 35 years in our approach to cancer therapy. To set the scene, it is first appropriate to describe the research and treatment philosophy for breast cancer before tamoxifen.In the 1960's, the use of combination cytotoxic chemotherapy for the treatment of breast cancer had moved to center stage in the wake of an abstract presented at the American Association for Cancer Research (4). The cytotoxic "cocktail" presented by Cooper, containing cyclophosphamide, methotrexate, 5 fluorouracil, vincristine and prednisone (CMFVP), produced a dramatic response rate of >80% in patients with advanced breast cancer. In the 1960's, there was every reason to believe that cancer would be curable if 1) the right drug Correspondence: V. Craig Jordan, OBE, PhD, DSc, Vice President and Research Director for Medical Sciences, Alfred G. Knudson Chair of Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, Phone: (215) Fax: (215) ...

show abstract

“…: ER positive breast cancer. However, the finding that long term tamoxifen treatment in animals with early mammary cancer i.e., a low tumor burden [18][19][20] could create a tumor-free state suggested longer was going to be better than shorter durations of adjuvant therapy. The laboratory observations and pilot clinical studies [21,22] were to prove remarkably effective as an approach to treat women with early node positive and node negative ER positive breast cancer.…”

mentioning

confidence: 99%

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

Jordan¹,

Brodie²

2007

Steroids

259

183

View full text Add to dashboard Cite

The enthusiasm with which the clinical community has embraced the use of antiestrogenic therapy to treat breast cancer is based upon the proven record of success that first the nonsteroidal antiestrogen tamoxifen and then the aromatase inhibitor have demonstrated in clinical trial. The reasons for the enthusiasm are obvious. Antihormonal therapy, particularly aromatase inhibition to create a "no estrogen state" in the postmenopausal breast cancer patient is effective, saves women's lives, is contributing successfully to reducing the national mortality from breast cancer, is relatively cheap and has fewer side effects and easy administration (oral) than any other anticancer strategy. However, the successful application of a therapeutic strategy to block the known growth stimulation property of estrogen in breast cancer was not greeted with such enthusiasm 40 years ago.Estrogen is essential for life. Without the critical role of estrogenic steroids, reproduction would not be possible. Based on emerging knowledge from laboratory studies, the value of modulating the steroid environment during the menstrual cycle was advanced to clinical testing during the 1950's as a means of oral contraception. The results of these studies were to change society forever.The Worcester Foundation for Experimental Biology is the place where Gregory Pincus established the scientific principles necessary to propose clinical testing of the oral contraceptive and M.C. Chang subsequently established the first protocols to perform in vitro fertilization. Simply stated, the Worcester Foundation was, at that time, the world center for steroid endocrinology and reproductive biology. Over the years, hundreds of scientists have trained at the Foundation and subsequently spread their knowledge throughout the world [1]. However, fashions in research change and new opportunities emerge.In 1971, President Nixon made a national commitment to seek a cure for cancer by signing the National Cancer Act. Mahlon Hoagland, the President of the Worcester Foundation, responded to the initiative by appointing Professor Elwood V. Jensen, Director of the Ben May Cancer Research Laboratory at the University of Chicago, to be a member of the Foundation's Scientific Advisory Board. Jensen had discovered the estrogen receptor (ER) as the putative mechanism of estrogen action in its target tissues [2]. The known link between estrogen and breast cancer suggested that "antiestrogenic strategies" might have potential as therapeutic Correspondence to: V. Craig Jordan, v.craig.jordan@fccc.edu. Present Address: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be d...

show abstract

Evaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model

Cited by 195 publications

References 21 publications

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

Tamoxifen: Catalyst for the change to targeted therapy

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

Contact Info

Product

Resources

About