Trilostane with hydrocortisone in treatment of metastatic breast cancer

Chu, Ping S.; Buzdar, Aman U.; Hortobágyi, Gabriel N.

doi:10.1007/bf01806523

Cited by 9 publications

(2 citation statements)

References 7 publications

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“…Trilostane (Modrenal) has also been used in the treatment of breast cancer [23,24,25] and is effective in crossover studies with the aromatase inhibitor aminoglutethimide [26]. A striking characteristic of trilostane is that it is a non-competitive inhibitor of ER function [27], leading to the possibility that ligands interacting with allosteric sites on ER may contribute to the overall complexity of the oestrogenic response, and independently modulate coactivator/repressor involvement.…”

Section: Introductionmentioning

confidence: 99%

Multiple Routes to Oestrogen Antagonism

et al. 2010

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Several lines of evidence attest to the existence of alternative ligand binding sites on the oestrogen receptor (ER), including non-competitive inhibition by trilostane or tamoxifen. It is possible that the inhibitory action of conventional oestrogen agonists at high concentrations may indicate that they too interact at alternative ER sites, albeit at low affinity. To test this possibility an oestrogen reporter assay was used to compare the activity of different oestrogens and antagonists in breast cancer and prostate cell lines. All four cell lines tested contained different amounts of oestrogen receptor α (ERα), ERβ, progesterone receptor and coregulator mRNA. Though differences were observed in response to stimulation and inhibition, these correlated only with the presence or absence of ERα, and not with the other components. Thus stimulation of the reporter by oestradiol and oestrone was biphasic in the breast cancer cells, while prostate cells were unable to respond. Only T47D cells were stimulated by oestriol or diethylstilboestrol, however reporter activity of all the cell lines was repressed by 10μM diethylstilboestrol. Reporter activity of MCF-7 cells was inhibited by tamoxifen, raloxifene and ICI 182,780, but stimulated by trilostane, yet all these antioestrogens inhibited agonist-stimulated activity. Trilostane also inhibited the agonism seen in cells co-treated with E2 and tamoxifen. It is clear that several of the compounds tested may have either agonist or antagonist effects under different conditions and at different concentrations, acting through ERα alone. Though biphasic dose response curves, or hormesis, have been attributed to various mechanisms, we here provide evidence that alternative ligand binding sites may contribute to this phenomenon.

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Section: Introductionmentioning

confidence: 99%

Multiple Routes to Oestrogen Antagonism

et al. 2010

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“…Trilostane (which was originally introduced as an inhibitor of 3-beta-hydroxysteroid dehydrogenase) [13] has also been used for treatment of hormone-responsive breast cancer [14][15][16] and, importantly, has proven efficacy in advanced post-menopausal breast cancer after development of acquired resistance to tamoxifen or the aromatase inhibitor aminoglutethimide [17]. Trilostane is a steroid that has direct effects on ER without displacing E2 from, or competing with E2 for, binding in the ER LBD [18].…”

Section: Introductionmentioning

confidence: 99%