Effects of CH4893237, a new orally active estrogen receptor downregulator, on breast cancer xenograft models with low serum estrogen levels

  • Authors:
    • Takaaki Yoneya
    • Toshiaki Tsunenari
    • Kenji Taniguchi
    • Yoshitake Kanbe
    • Kazumi Morikawa
    • Hisafumi Yamada-Okabe
    • Yeon-Ho Lee
    • Mee-Hyun Lee
    • Lae-Sung Kwon
  • View Affiliations

  • Published online on: March 1, 2009     https://doi.org/10.3892/or_00000280
  • Pages: 747-755
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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 ERα and ERβ 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 ERα and ERβ 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.

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March 2009
Volume 21 Issue 3

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Yoneya T, Tsunenari T, Taniguchi K, Kanbe Y, Morikawa K, Yamada-Okabe H, Lee Y, Lee M and Kwon L: Effects of CH4893237, a new orally active estrogen receptor downregulator, on breast cancer xenograft models with low serum estrogen levels. Oncol Rep 21: 747-755, 2009
APA
Yoneya, T., Tsunenari, T., Taniguchi, K., Kanbe, Y., Morikawa, K., Yamada-Okabe, H. ... Kwon, L. (2009). Effects of CH4893237, a new orally active estrogen receptor downregulator, on breast cancer xenograft models with low serum estrogen levels. Oncology Reports, 21, 747-755. https://doi.org/10.3892/or_00000280
MLA
Yoneya, T., Tsunenari, T., Taniguchi, K., Kanbe, Y., Morikawa, K., Yamada-Okabe, H., Lee, Y., Lee, M., Kwon, L."Effects of CH4893237, a new orally active estrogen receptor downregulator, on breast cancer xenograft models with low serum estrogen levels". Oncology Reports 21.3 (2009): 747-755.
Chicago
Yoneya, T., Tsunenari, T., Taniguchi, K., Kanbe, Y., Morikawa, K., Yamada-Okabe, H., Lee, Y., Lee, M., Kwon, L."Effects of CH4893237, a new orally active estrogen receptor downregulator, on breast cancer xenograft models with low serum estrogen levels". Oncology Reports 21, no. 3 (2009): 747-755. https://doi.org/10.3892/or_00000280