Phase I/II study of the anti-oestrogen zindoxifene (D16726) in the treatment of advanced breast cancer. A Cancer Research Campaign Phase I/II Clinical Trials Committee study

Stein, Robert; Dowsett, Mitchell; Cunningham, David; Davenport, James H.; Ford, H. T.; Gazet, J C; Angerer, E. von; Coombes, R. Charles

doi:10.1038/bjc.1990.99

Cited by 23 publications

(10 citation statements)

References 18 publications

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“…(4)). It was designed by adding an alkylaminoethoxyphenyl side chain to zindoxifene (D-16726), a 2-phenylindol based SERM which failed as a treatment for breast cancer [165]. Pipendoxifene, also named ERA-923, mimics the structure of raloxifene and is devoid of uterotrophic activities in immature rats and ovariectomized mice compared to raloxifene [166].…”

Section: New Sermsmentioning

confidence: 99%

Potential of Selective Estrogen Receptor Modulators as Treatments and Preventives of Breast Cancer

Peng¹,

Sengupta²,

Jordan

2009

ACAMC

117

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Estrogen plays vital roles in human health and diseases. Estrogen mediates its actions almost entirely by binding to estrogen receptors (ER), alpha and beta which further function as transcription factors. Selective estrogen receptor modulators (SERMs) are synthetic molecules which bind to ER and can modulate its transcriptional capabilities in different ways in diverse estrogen target tissues. Tamoxifen, the prototypical SERM, is extensively used for targeted therapy of ER positive breast cancers and is also approved as the first chemo-preventive agent for lowering breast cancer incidence in high risk women. The therapeutic and preventive efficacy of tamoxifen was initially proven by series of experiments in the laboratory which laid the foundation of its clinical use. Unfortunately, use of tamoxifen is associated with de-novo and acquired resistance and some undesirable side effects. The molecular study of the resistance provides an opportunity to precisely understand the mechanism of SERM action which may further help in designing new and improved SERMs. Recent clinical studies reveal that another SERM, raloxifene, which is primarily used to treat post-menopausal osteoporosis, is as efficient as tamoxifen in preventing breast cancers with fewer side effects. Overall, these findings open a new horizon for SERMs as a class of drug which not only can be used for therapeutic and preventive purposes of breast cancers but also for various other diseases and disorders. Major efforts are therefore directed to make new SERMs with a better therapeutic profile and fewer side effects.

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Section: New Sermsmentioning

confidence: 99%

Potential of Selective Estrogen Receptor Modulators as Treatments and Preventives of Breast Cancer

Peng¹,

Sengupta²,

Jordan

2009

ACAMC

117

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“…The anti-oestrogen zindoxifene (D16726) is a 2-phenylindole structure that was previously shown to have oestrogenic activity in the uterus [60] but was inactive in a breast cancer trial [61]. By making rigid the alkylamino side chain, similar to the structure of raloxifene and EM-800, a new indole SERM called ERA-923 was created that was devoid of uterotrophic activity in immature rats when compared with raloxifene and ZK119010 [62].…”

Section: 'Fixed Ring' Sermsmentioning

confidence: 99%

Endocrinology and hormone therapy in breast cancer: Selective oestrogen receptor modulators and downregulators for breast cancer – have they lost their way?

Johnston

2005

Breast Cancer Res

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119 AI = aromatase inhibitor; ER = oestrogen receptor; LTED = long-term oestrogen deprivation; PgR = progesterone receptor; SERD = selective oestrogen receptor downregulator; SERM = selective oestrogen receptor modulator.Available online http://breast-cancer-research.com/contents/7/3/119 AbstractAlthough tamoxifen has been an effective treatment for breast cancer, several novel anti-oestrogen compounds have been developed with a reduced agonist profile on breast and gynaecological tissues. These include selective oestrogen receptor modulators (SERMs; both 'tamoxifen-like' and 'fixed-ring' SERMs) and selective oestrogen receptor downregulators (SERDs), although none has proved superior in efficacy to tamoxifen in various advanced breast cancer trials. Thus, many have questioned whether a need for SERMs in breast cancer still exists, although chemoprevention remains a possible niche setting. In contrast, SERDs may have useful efficacy following aromatase inhibitors because of their unique mechanism of action, and clinical trials to determine their optimal use or sequence are ongoing. IntroductionOestrogen has important physiological effects on the growth and function of hormone-dependent tissues, including breast epithelium, uterus, vagina and ovaries. In addition, oestrogen preserves bone mineral density and reduces the risk for osteoporosis, protects the cardiovascular system by reducing cholesterol levels, and modulates cognitive function and behaviour. Tamoxifen is a nonsteroidal anti-oestrogen that antagonizes the action of oestrogen and is effective in both the treatment [1,2] and prevention of breast cancer [3]. Although concerns were raised regarding the potential antioestrogenic effects on normal tissues, paradoxically tamoxifen acts as an oestrogen on bone, blood lipids and the endometrium [4]. In the adjuvant and prevention settings, this may increase the risk for endometrial cancer in women taking tamoxifen, although the risk has been perceived to be small in relation to the substantial benefit from reduction in breast cancer related events [5]. Likewise, breast epithelial cells and established carcinomas adapt to chronic anti-oestrogen exposure and develop resistance to tamoxifen, which may also result from the drug's partial agonistic activity stimulating tumour regrowth [6].The term 'selective oestrogen receptor modulator' (SERM) refers to the capacity of separate anti-oestrogens to exert alternative effects on various oestrogen regulated targets. Over the past 10-15 years several strategies were employed to improve or alter the agonist/antagonist profile of tamoxifen. An understanding of structure-function relationships led to chemical modifications of tamoxifen, either by altering the side chains to produce new tamoxifen analogues such as toremifene, idoxifene, droloxifene, lasofoxifene and TAT-59; or by altering the nonsteroidal triphenylethylene ring structure of tamoxifen to produce a nonsteroidal 'fixed ring' structure such as the benzothiophene derivatives raloxifene and arzoxifene, the benzo...

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“…Zindoxifene is an indole derivative of tamoxifen. A phase I/II trial of zindoxifene was reported by Stein and colleagues 37 from the United Kingdom. The doses ranged from 10 mg/day to 100 mg/day orally.…”

Section: Zindoxifenementioning

confidence: 99%

New Hormonal Therapies for Breast Cancer

Minton

1999

Cancer Control

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BACKGROUND: There has been an explosion in the development of hormonal therapies for the treatment of breast cancer. Several new agents have been approved for the treatment of breast cancer in the metastatic setting, and trials are ongoing in the adjuvant and prevention setting to improve hormonal therapy for the prevention and treatment of breast cancer. METHODS: The literature on new hormonal therapies for the treatment of breast cancer is reviewed, with an emphasis on newer agents. RESULTS: Two antiestrogens are now approved in the United States for the treatment of metastatic breast cancer. Other antiestrogens have activity in metastatic breast cancer as well as in osteoporosis. Newer pure antiestrogens may overcome resistance to tamoxifen. Several aromatase inhibitors are available for the treatment of metastatic breast cancer. CONCLUSIONS: Many hormonal agents are now available for both adjuvant and advanced disease settings. Developments will depend on clarifying mechanisms of resistance to antiestrogens and identifying new classes of agents that lack cross-resistance to standard therapy.

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Phase I/II study of the anti-oestrogen zindoxifene (D16726) in the treatment of advanced breast cancer. A Cancer Research Campaign Phase I/II Clinical Trials Committee study

Cited by 23 publications

References 18 publications

Potential of Selective Estrogen Receptor Modulators as Treatments and Preventives of Breast Cancer

Potential of Selective Estrogen Receptor Modulators as Treatments and Preventives of Breast Cancer

Endocrinology and hormone therapy in breast cancer: Selective oestrogen receptor modulators and downregulators for breast cancer – have they lost their way?

New Hormonal Therapies for Breast Cancer

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