title: Effects of CH4893237, a new orally active estrogen receptor downregulator, on breast cancer xenograft models with low serum estrogen levels.
abstract: We compared the antitumor efficacy and estrogen receptor (ER) degradation of CH4893237, a new orally active selective ER downregulator, with fulvestrant and tamoxifen in human breast cancer xenografts with low levels of serum estrogen (E2) (50.6, 22.9 and <16.7 pg/ml), equivalent to the ranges in postmenopausal or aromatase inhibitor-treated breast cancer patients. In addition, using proteolysis assays, we tested the conformational changes induced in ERalpha and ERbeta by CH4893237, fulvestrant, and 4-OH tamoxifen (4OHT). In ZR-75-1 xenografts with 50.6 pg/ml E2, CH4893237 (100 and 300 mg/kg/day p.o.) as well as fulvestrant (1 and 3 mg/body/week s.c.) showed complete growth inhibition (>90%) and tamoxifen (30 and 100 mg/kg/day p.o.) showed moderate tamoxifen resistance. The antitumor activity of CH4893237 (300 mg/kg) was the same as that of fulvestrant (3 mg/body) but the rate of ER degradation induced by CH4893237 (300 mg/kg) was significantly stronger than that of fulvestrant (3 mg/body) (94.3 vs. 85.5%, P<0.01). In Br-10 xenografts with 22.9 pg/ml E2, CH4893237 (30 mg/kg) and fulvestrant (1 mg/body) showed potent growth inhibition (>70%) whereas tamoxifen (1, 10 and 100 mg/kg) showed strong tamoxifen resistance. In Br-10 xenografts with ovariectomized-level E2 (<16.7 pg/ml), tamoxifen (30 mg/kg) increased the tumor volume but CH4893237 (30 mg/kg) showed no agonistic activity. In the ERalpha and ERbeta proteolysis assays, the band pattern for CH4893237 was different from fulvestrant. Thus, CH48793237 showed potent antitumor efficacies without agonistic activity and superior ER degradation in human breast cancer xenografts with low serum E2. Furthermore, the proteolysis studies suggest that CH4893237 induces conformational changes of ER different from those induced by fulvestrant. Therefore, CH4893237 alone or in combination with an aromatase inhibitor may be an efficient treatment for postmenopausal breast cancer patients.
authors.affiliation: Kamakura Research Laboratories, Kanagawa 247-8530, Japan. yoneyatka@chugai-pharm.co.jp
authors.forename: Takaaki
authors.initials: T
authors.lastname: Yoneya
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tsunenari
authors.forename: Kenji
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Yoshitake
authors.initials: Y
authors.lastname: Kanbe
authors.forename: Kazumi
authors.initials: K
authors.lastname: Morikawa
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Yamada-Okabe
authors.forename: Yeon-Ho
authors.initials: YH
authors.lastname: Lee
authors.forename: Mee-Hyun
authors.initials: MH
authors.lastname: Lee
authors.forename: Lae-Sung
authors.initials: LS
authors.lastname: Kwon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004967:Estrogens / Q000097:blood*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C508478:CH 4893237; D004967:Estrogens; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D000077267:Fulvestrant; D004958:Estradiol