Yoneya Takaaki, Tsunenari Toshiaki, Taniguchi Kenji, Kanbe Yoshitake, Morikawa Kazumi, Yamada-Okabe Hisafumi, Lee Yeon-Ho, Lee Mee-Hyun, Kwon Lae-Sung
Kamakura Research Laboratories, Kanagawa 247-8530, Japan.
Oncol Rep. 2009 Mar;21(3):747-55.
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.
我们将一种新型口服活性选择性雌激素受体下调剂CH4893237与氟维司群和他莫昔芬在血清雌激素（E2）水平较低（50.6、22.9和<16.7 pg/ml）的人乳腺癌异种移植模型中进行了抗肿瘤疗效和雌激素受体（ER）降解的比较，这一雌激素水平范围与绝经后或接受芳香化酶抑制剂治疗的乳腺癌患者相当。此外，我们通过蛋白水解试验，测试了CH4893237、氟维司群和4-羟基他莫昔芬（4OHT）诱导雌激素受体α（ERα）和雌激素受体β（ERβ）的构象变化。在E2水平为50.6 pg/ml的ZR-75-1异种移植模型中，CH4893237（100和300 mg/kg/天，口服）以及氟维司群（1和3 mg/只/周，皮下注射）均显示出完全生长抑制（>90%），而他莫昔芬（30和100 mg/kg/天，口服）则表现出中度他莫昔芬耐药。CH4893237（300 mg/kg）的抗肿瘤活性与氟维司群（3 mg/只）相同，但CH4893237（300 mg/kg）诱导的ER降解率显著高于氟维司群（3 mg/只）（94.3%对85.5%，P<0.01）。在E2水平为22.9 pg/ml的Br-10异种移植模型中，CH4893237（30 mg/kg）和氟维司群（1 mg/只）显示出强效生长抑制（>70%），而他莫昔芬（1、10和100 mg/kg）则表现出强他莫昔芬耐药。在E2水平处于去卵巢水平（<16.7 pg/ml）的Br-10异种移植模型中，他莫昔芬（30 mg/kg）使肿瘤体积增大，但CH4893237（30 mg/kg）未表现出激动活性。在ERα和ERβ蛋白水解试验中，CH4893237的条带模式与氟维司群不同。因此，在血清E2水平较低的人乳腺癌异种移植模型中，CH48793237显示出强效抗肿瘤疗效且无激动活性，并具有卓越的ER降解能力。此外，蛋白水解研究表明，CH4893237诱导的ER构象变化与氟维司群诱导的不同。因此，CH4893237单独使用或与芳香化酶抑制剂联合使用可能是绝经后乳腺癌患者的一种有效治疗方法。
