Disease relevance of CB 7432

• Idoxifene: report of a phase I study in patients with metastatic breast cancer [1].
• In this study the ability of five novel anti-oestrogens [4-iodotamoxifen, pyrrolidino-4-iodotamoxifen, ethyl bromide tamoxifen (EBTx), ICI 164,384 (ICI 164) and ICI 182,780] to alter drug toxicity to multidrug resistant cell lines have been compared [2].
• AA was induced in Lewis rats with Mycobacterium butyricum in paraffin oil injected into the base of the tail, and the animals were treated with idoxifene prophylactically (days 0-21) or therapeutically (days 10-21) [3].
• Effects of a new antioestrogen, idoxifene, on cisplatin- and doxorubicin-sensitive and -resistant human ovarian carcinoma cell lines [4].
• This study reports on the antioxidant and antiapoptotic role of idoxifene and E2 in the DMN model of hepatic fibrosis [5].

High impact information on CB 7432

• The patients took part in one of 3 neoadjuvant trials of hormonal therapy with a SERM (tamoxifen or idoxifene) or an aromatase inhibitor (anastrozole or vorozole) [6].
• Both tamoxifen and idoxifene initially induced ER expression, whereas prolonged therapy with tamoxifen significantly reduced progesterone receptor levels [7].
• Sustained induction of apoptosis may contribute to prolonged antagonism of E2-dependent growth, and it occurred to a greater extent following 3 months of idoxifene, compared to tamoxifen [7].
• Idoxifene antagonizes estradiol-dependent MCF-7 breast cancer xenograft growth through sustained induction of apoptosis [7].
• Both anti-E2s inhibited cell proliferation and caused a significant 3-fold induction of apoptosis in E2 supported tumors after 1 week, which was maintained for 3 months with idoxifene (3.1 versus 0.48% compared to E2 controls) but decreased back to baseline in tumors treated with tamoxifen (0.69%) [7].

Chemical compound and disease context of CB 7432

• In advanced breast cancer clinical data exist for three first-generation SERMs (toremifene, droloxifene, idoxifene), which are related to the triphenylethylene structure of tamoxifen [8].
• Levormeloxifene and idoxifene trials noted a higher proportion of surgery for pelvic organ prolapse in treated versus untreated women [9].
• New SERMs to treat and prevent breast cancer, osteoporosis, and cardiovascular disease are undergoing clinical development, including idoxifene, droloxifene, ospemifene, lasofoxifene, arzoxifene, and MDL 103,323 [10].

Biological context of CB 7432

• Idoxifene also inhibits calmodulin, a calcium-binding protein that is involved in cell signal transduction pathways [7].
• Idoxifene (0.5 mg/kg x day) completely prevented loss of both lumbar and proximal tibial bone mineral density (BMD) [11].
• Idoxifene also stimulates osteoclast apoptosis, and these pleiotropic effects ultimately could contribute to the maintenance of bone homeostasis [11].
• Toremifene resulted in aneuploidy in 50 +/- 7% of the cells examined and idoxifene induced a 57 +/- 4% aneuploidy compared with the 85 +/- 7% level induced by tamoxifen [12].
• Analysis of electron micrographs of cultures treated with these antiestrogens demonstrated a range of phenotypes including multipolar spindles in toremifene-treated rats and condensed chromosomes in the presence of an intact nuclear envelope in occasional idoxifene-treated rat hepatocytes [12].

Anatomical context of CB 7432

• In human hepatocytes, neither idoxifene nor tamoxifen induced detectable levels of DNA adducts [13].
• In the uterus, idoxifene has a pharmacologically favorable profile, lacking agonist and therefore growth-promoting activity [11].
• Together with its cholesterol lowering effect and lack of uterotrophic activity, these data suggest that idoxifene may be effective in the prevention of osteoporosis and other postmenopausal diseases without producing unwanted estrogenic effects on the endometrium [11].
• In one of four cell lines (CH1), synergism between idoxifene and cisplatin was observed by median effect analysis [4].
• 2. In order to investigate vascular effects of selective oestrogen receptor modulators, we examined the impact of idoxifene on production of reactive oxygen species as well as AT1 receptor expression in vascular smooth muscle cells (VSMC) [14].

Associations of CB 7432 with other chemical compounds

• Binding studies showed that both 4-iodotamoxifen and pyrrolidino-4-iodotamoxifen and 2.5-fold higher affinities for the estrogen receptor compared with tamoxifen [15].
• In the incidental therapy scenario, we have conducted a number of studies to evaluate the biological effects of raloxifene, idoxifene, fulvestrant (in comparison with tamoxifen), and the aromatase inhibitor 4-hydroxyandrostenedione [16].
• Treatment of the rings with N(omega)-nitro-L-arginine methyl ester completely blocked idoxifene- and 17 beta-estradiol-induced vasorelaxation [17].
• Raloxifene and idoxifene are selective estrogen receptor modulators (SERMs) that exhibit tissue-specific agonist or antagonist properties via interactions with the estrogen receptor (ER) [18].
• 4. Confocal laserscanning microscopy using the redox sensitive marker 2',7'-dichlorofluorescein (DCF) and measurement of NAD(P)H oxidase activity in cell homogenates revealed that idoxifene effectively blunted the angiotensin II-induced production of reactive oxygen species [14].

Gene context of CB 7432

• Hepatocytes possessed functional ER-beta, but not ER-alpha, to respond directly to idoxifene and E2 [19].
• Our results indicate that idoxifene and E2 could enhance antiapoptotic activity through ER-beta during oxidative damage in hepatocytes [19].
• The percentage of Ki67-positive cells fell from a mean 19.7 +/- 2.7% (SE) to 13.4 +/- 3.4% in idoxifene-treated ER-positive tumors (n = 30; P = 0.0043), but there was no significant effect in placebo-treated ER-positive tumors (n = 27) [20].
• Compared to tamoxifen, idoxifene is metabolically more stable, with a higher relative binding affinity for the ER and reduced agonist activity on breast and uterine cells [7].
• In this study, we assessed the effect of idoxifene on biological markers of cell proliferation (Ki67) and apoptosis (TdT-mediated dUTP-biotin nick end labeling), and estrogen and progesterone receptor (ER/PR) expression was also evaluated [20].

Analytical, diagnostic and therapeutic context of CB 7432

• In this study, the abilities of idoxifene and tamoxifen to antagonize E2-dependent MCF-7 xenograft growth in oophorectomized athymic mice were compared [7].
• The described method uses short, small-bore columns, high flow rates, and elevated HPLC column temperatures to perform LC separations of idoxifene and its metabolite within 10 s/sample [21].
• In an intervention study, idoxifene (0.5 and 2.5 mg/kg x day) completely prevented further loss of both lumbar and proximal tibial BMD during a 2-month treatment period commencing 1 month after surgery, when significant loss of BMD had occurred in the Ovx control group [11].
• Idoxifene, a tissue-specific selective estrogen receptor modulator, was evaluated in male and female rats and female rabbits after oral administration for effects on fertility and/or embryo-fetal development [22].
• High-resolution MRI and micro-FE for the evaluation of changes in bone mechanical properties during longitudinal clinical trials: application to calcaneal bone in postmenopausal women after one year of idoxifene treatment [23].

References