Derivatives of tamoxifen. Dependence of antiestrogenicity on the 4-substituent

McCague, Raymond; Leclercq, Guy; Legros, Nicole; J, Goodman; Gm, Blackburn; Jarman, Michael; Ab, Foster

doi:10.1021/jm00132a006

Cited by 99 publications

(69 citation statements)

References 4 publications

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“…The N-allylic substitution on naloxone occupies the same region as D ring, which may be responsible for its antagonistic activity (43,44). Indeed, antagonistic activity of naloxone is corroborated by our observations that naloxone inhibits E2-induced activation of nuclear ERa directly in the nuclear fraction of the cells devoid of any membrane receptors.…”

Section: Discussionsupporting

confidence: 74%

Naloxone acts as an antagonist of estrogen receptor activity in MCF-7 cells

Farooqui

Geng

Stephenson

et al. 2006

Molecular Cancer Therapeutics

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Estrogen promotes the growth of breast cancer via estrogen receptors (ER). Earlier studies showed that the opioid receptor antagonist naloxone inhibits MCF-7 breast cancer growth in mice. We examined the cellular and molecular mechanism of naloxone antagonism of ERA activity in human MCF-7 cells. Naloxone (100 nmol/L) inhibited 17B-estradiol (E2) -induced (10 nmol/L) MCF-7 cell proliferation by 65% and mitogen-activated protein kinase/extracellular signal-regulated kinase phosphorylation. Naloxone blocked the E2-induced activation of ERA, with 85% inhibition after 5 minutes and 100% recovery after 60 minutes. This assay is based on quantitation of E2-activated nuclear ERA binding to the immobilized coactivator peptide. A significant decrease in E2-induced ERA transactivation was observed in the presence of naloxone in the estrogen response element-luciferase reporter assay (P < 0.05, E2 versus E2 + naloxone). Naloxone also blocked E2-induced down-regulation of ERA mRNA at 30 minutes and 6 hours. Although naloxone inhibits ERA activity directly, it also induces a cross-talk between Mopioid receptor (MOR) and ERA. Immunoprecipitates with anti-MOR antibody showed the presence of ERA in cells incubated with E2 in the presence of naloxone but not in cells incubated with E2 or naloxone alone. Higher amounts of ERA associated with MOR after 60 minutes compared with 10 minutes of incubation. Naloxone inhibited E2-bovine serum albumin-FITC binding to plasma membraneassociated ERA and also inhibited the direct binding of

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Section: Discussionsupporting

confidence: 74%

Naloxone acts as an antagonist of estrogen receptor activity in MCF-7 cells

Farooqui

Geng

Stephenson

et al. 2006

Molecular Cancer Therapeutics

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“…Idoxifene was synthesized as described previously (McCague et al, 1989) and tamoxifen was a gift from Dr A Wakeling (Zeneca, UK). Idoxifene and tamoxifen were dissolved in peanut oil.…”

Section: Drug Administration and Tumour Measurementmentioning

confidence: 99%

Idoxifene is equipotent to tamoxifen in inhibiting mammary carcinogenesis but forms lower levels of hepatic DNA adducts

Pace

Jarman²,

Phillips³

et al. 1997

Br J Cancer

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Summary Tamoxifen is an effective agent preventing mammary carcinogenesis in rats but causing liver tumours. Idoxifene is a more potent antioestrogen and is effective in patients with advanced breast cancer. We therefore compared the effects of idoxifene with tamoxifen on mammary carcinogenesis and hepatic DNA adduct formation. To do this, we undertook a study designed to compare tamoxifen with idoxifene as a chemopreventive agent in rats inoculated with Mmethyinitrosourea (MNU) and also measured hepatic adduct formation. We examined the time to mammary tumour development in 272 female Ludwig/Wistar/Olac rats treated with MNU followed by tamoxifen (5 mg kg-'), equimolar idoxifene or vehicle three times a week for up to 24 weeks. To determine duration of effect, a second study was carried out whereby all of the 129 animals surviving at the end of treatment were entered into a surveillance programme for 27 weeks after the end of the administration period. Hepatic DNA adduct formation was examined by 32P-postlabelling in a group of rats after 24 weeks' treatment. In the first study, both idoxifene and tamoxifen were effective in preventing tumour growth as only 2 out of 21 (10%) MNU and vehicle-treated animals were alive and tumour free after 24 weeks compared with 13 out of 22 (59%) animals receiving MNU followed by idoxifene or tamoxifen (P < 0.001). The second study showed that, in both idoxifene-and tamoxifen-treated animals, a progressive regrowth of tumours occurred after cessation of therapy, as by the end of the observation period only four idoxifene-treated animals and one tamoxifen-treated animal were free from disease. In the subset of animals tested, tamoxifen-treated animals had approximately 100 times higher levels of DNA hepatic adducts than idoxifene-treated animals. Adducts were not seen in the control group. These results indicate that idoxifene is as effective a chemopreventive agent as tamoxifen in the rat while causing only very low levels of DNA adducts in liver tissue and suggest that idoxifene may be a well-tolerated chemopreventive agent in women who are at increased risk of breast cancer.

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“…Analogues of tamoxifen that include an iodine atom at position 4 have been found to have increased affinity for ER (McCague et al, 1989). Such compounds cannot undergo glucuronidation via 4-hydroxylation, which probably aids the excretion of tamoxifen (McCague et al, 1990a), and, unlike trans-4-hydroxytamoxifen, they cannot isomerize to the cis isomer, which has much weaker anti-oestrogenic properties for tamoxifen, while retaining partial agonist activity (Murphy et al, 1990).…”

mentioning

confidence: 99%

The novel anti-oestrogen idoxifene inhibits the growth of human MCF-7 breast cancer xenografts and reduces the frequency of acquired anti-oestrogen resistance

Johnston

Riddler²,

Haynes³

et al. 1997

Br J Cancer

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Summary The effect of idoxifene, a novel anti-oestrogen with less agonist activity than tamoxifen, was compared with that of tamoxifen on the growth of hormone-dependent MCF-7 breast cancer xenografts. Forty tumours were established with oestradiol support in ovariectomized athymic mice, allowed to grow to a median volume of 420 mm3 and then continued with oestradiol, no support, tamoxifen or idoxifene delivered by 1.5-cm silastic capsule. Tumour regression occurred with both anti-oestrogens, although maximum regression was observed following oestradiol withdrawal alone. While prolonged anti-oestrogen therapy was associated with static growth, tumour volumes were significantly lower with idoxifene (P=0.01). After 6 months, 0/10 idoxifene-treated tumours developed acquired resistance compared with 3/10 tumours treated with tamoxifen. In separate experiments, 94 animals were treated initially with oestradiol, tamoxifen, idoxifene or placebo following implantation with 1-mm3 pieces of either wild-type (WT) or tamoxifen-resistant (TR) MCF-7 tumour. After 4 months, only 1/11 WT tumours became established with idoxifene compared with 4/11 with tamoxifen, 8/12 with oestradiol and 0/12 with placebo. Likewise, fewer TR tumours were supported by idoxifene (3/12) than by tamoxifen (8/12) or oestrogen (11/12). These data indicate that, compared with tamoxifen, idoxifene shows reduced growth support of MCF-7 xenografts and may share only partial cross-resistance. Furthermore, the development of acquired anti-oestrogen resistance may be reduced during long-term idoxifene therapy. The drug's reduced agonist activity may, in part, explain these observations and indicate a preferable biochemical profile for breast cancer treatment.

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Derivatives of tamoxifen. Dependence of antiestrogenicity on the 4-substituent

Cited by 99 publications

References 4 publications

Naloxone acts as an antagonist of estrogen receptor activity in MCF-7 cells

Naloxone acts as an antagonist of estrogen receptor activity in MCF-7 cells

Idoxifene is equipotent to tamoxifen in inhibiting mammary carcinogenesis but forms lower levels of hepatic DNA adducts

The novel anti-oestrogen idoxifene inhibits the growth of human MCF-7 breast cancer xenografts and reduces the frequency of acquired anti-oestrogen resistance

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