Effect of the aromatase inhibitor, MEN 11066, on growth of two different MCF-7 sublines.
The racemate compound MEN 11066 (1-[(benzofuran-2-yl)(4'-cyanophenyl)methyl]-1H-1,2,4-triazole) and its enantiomers, (+)-MEN 11623 and (-)-MEN 11622, showed potent and selective aromatase activity on human placental microsomes. In addition, to better evaluate their potency as anticancer drugs, the compounds were assayed on testosterone-induced cell proliferation to measure their ability in inhibiting oestrogen-dependent tumour growth. Two different sublines originated from the human breast carcinoma MCF-7 were used. One, named MCF-7(tumour aromatase) (TA), that had maintained its intrinsic aromatase activity, was more sensitive to estradiol or testosterone-induced growth than the second subline named MCF-7(human placental aromatase) (hPA). The latter had been transfected with the human placental aromatase cDNA, after recognizing that the parental cells had aromatase activity reduced to undetectable levels. The MEN compounds completely reverted the testosterone-induced proliferation in both MCF-7(TA) and MCF-7(hPA) cells, while they did not affect the estradiol-triggered proliferation as a proof of their specificity for aromatase enzyme. Interestingly, MCF-7(TA) cells were more susceptible to the effects of aromatase inhibitors than the MCF-7(hPA) cell. These data suggest the efficacy of aromatase inhibitors in breast cancer when the growth dependency from oestrogen is high and a relatively low aromatase activity may be extremely important for tumour development.
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Department of Pharmacology, Menarini Ricerche S.p.A., Via Tito Speri, 10 00040 Pomezia, Rome, Italy. pharmacology@menarini-ricerche.it
Criscuoli
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Lippi
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Muratori
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Mauro
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Maggi
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D000735:Androstenedione / Q000378:metabolism / Q000494:pharmacology; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D004970:Estrone / Q000494:pharmacology; D005260:Female; D006801:Humans; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010920:Placenta / Q000187:drug effects / Q000201:enzymology; D013237:Stereoisomerism; D013739:Testosterone / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D014316:Tritium; D014407:Tumor Cells, Cultured
D047072:Aromatase Inhibitors; D001572:Benzofurans; D004791:Enzyme Inhibitors; C419868:MEN 11066; D014230:Triazoles; D014316:Tritium; D004970:Estrone; D013739:Testosterone; D000735:Androstenedione; D004958:Estradiol; D004247:DNA; D001141:Aromatase