title: Comparison of the selective estrogen receptor modulator arzoxifene (LY353381) with tamoxifen on tumor growth and biomarker expression in an MCF-7 human breast cancer xenograft model.
abstract: Arzoxifene (ARZ) is a selective estrogen receptor (ER) modulator with greater bioavailability than raloxifene which is being developed as treatment for breast cancer. We have used an in vivo model of hormone-sensitive breast cancer to study the growth-inhibitory and pharmacodynamic effects of ARZ in comparison with the most widely used antiestrogen, tamoxifen (TAM). We compared the abilities of ARZ and TAM to antagonize the estrogen (E2)-dependent growth of MCF-7 human breast cancer xenografts in oophorectomized athymic mice. At four different time points over 28 days, we studied their time-related pharmacodynamic effects on biomarkers of tumor growth (cell proliferation/death measured by Ki-67 and apoptosis scores), cell cycle activity (cyclin D1 and p27(kip1)), and hormone-regulated gene expression (ERalpha, progesterone receptor, and pS2). Although maximal growth inhibition was seen after E2 withdrawal, ARZ and TAM induced significant and similar inhibition of E2-stimulated tumor growth. Inhibition of growth was reflected by changes in the tumor growth index (ratio posttreatment/pretreatment Ki-67/apoptosis scores). ARZ and TAM resulted in a significant (P < 0.001) increase in ER expression and reduction in progesterone receptor expression, whereas changes in cyclin D1 score were inversely related to p27(kip1) score. A significant but delayed biological effect was observed with a 10-fold lower dose of ARZ. These results show that ARZ is an effective antagonist of E2-stimulated breast cancer growth with similar growth-inhibitory and pharmacodynamic effects to TAM in this model.
authors.affiliation: Academic Department of Biochemistry, The Royal Marsden NHS Trust, Fulham Road, London SW3 6JJ, U.K.
authors.forename: Simone
authors.initials: S
authors.lastname: Detre
authors.forename: Sharon
authors.initials: S
authors.lastname: Riddler
authors.forename: Janine
authors.initials: J
authors.lastname: Salter
authors.forename: Roger
authors.initials: R
authors.lastname: A'Hern
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.forename: Stephen R D
authors.initials: SR
authors.lastname: Johnston
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D014176:Protein Biosynthesis; D011506:Proteins; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis; D020845:Selective Estrogen Receptor Modulators / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013629:Tamoxifen / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013876:Thiophenes / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D010880:Piperidines; D011506:Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D020845:Selective Estrogen Receptor Modulators; C051838:TFF1 protein, human; D013876:Thiophenes; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D013629:Tamoxifen; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C115121:LY 353381