Abstract
Aromatase inhibitors in clinical use block the biosynthesis of estrogens. Hydrolysis of estrone 3-sulfate by steroid sulfatase is an important additional source of tumor estrogen, and blockade of both enzymes should provide a more effective endocrine therapy. Sulfamoylated derivatives of the aromatase inhibitor YM511 inhibited sulfatase and aromatase in JEG-3 cells with respective IC(50) values of 20-227 and 0.82-100 nM (cf. letrozole, 0.89 nM). One dual inhibitor was potent against both enzymes in vivo, validating the concept.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Aromatase Inhibitors*
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Arylsulfatases / antagonists & inhibitors*
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Cell Line
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Estradiol / analysis
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Estradiol / blood
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Estrogen Antagonists / chemical synthesis
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Estrogen Antagonists / chemistry
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Estrogen Antagonists / pharmacology
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Female
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Humans
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Liver / chemistry
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Rats
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Rats, Wistar
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Steryl-Sulfatase
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Antineoplastic Agents
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Aromatase Inhibitors
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Enzyme Inhibitors
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Estrogen Antagonists
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Estradiol
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Arylsulfatases
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Steryl-Sulfatase