4.5 Article

Antitumor activity of Z-endoxifen in aromatase inhibitor-sensitive and aromatase inhibitor-resistant estrogen receptor-positive breast cancer

期刊

BREAST CANCER RESEARCH
卷 22, 期 1, 页码 -

出版社

BMC
DOI: 10.1186/s13058-020-01286-7

关键词

Z-endoxifen; Tamoxifen; Tumor growth in vivo; Estrogen-regulated genes; AI-resistant and AI-sensitive ER plus breast cancer; Signaling kinase

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资金

  1. Mayo Clinic Breast Cancer Specialized Program of Research Excellence Grant [P50CA 116201, R01 CA133049-01, R01 AR068275]
  2. Regis Foundation
  3. Prospect Creek Foundation
  4. George M. Eisenberg Foundation for Charities

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Background: The tamoxifen metabolite, Z-endoxifen, demonstrated promising antitumor activity in endocrine-resistant estrogen receptor-positive (ER+) breast cancer. We compared the antitumor activity of Z-endoxifen with tamoxifen and letrozole in the letrozole-sensitive MCF7 aromatase expressing model (MCF7AC1), as well as with tamoxifen, fulvestrant, exemestane, and exemestane plus everolimus in a letrozole-resistant MCF7 model (MCF7LR). Methods: MCF7AC1 tumor-bearing mice were randomized to control (no drug), letrozole (10 mu g/day), tamoxifen (500 mu g/day), or Z-endoxifen (25 and 75 mg/kg). Treatment in the letrozole arm was continued until resistance developed. MCF7LR tumor-bearing mice were then randomized to Z-endoxifen (50 mg/kg) or tamoxifen for 4 weeks and tumors harvested for microarray and immunohistochemistry analysis. The antitumor activity of Z-endoxifen in the MCF7LR tumors was further compared in a second in vivo study with exemestane, exemestane plus everolimus, and fulvestrant. Results: In the MCF7AC1 tumors, both Z-endoxifen doses were significantly superior to control and tamoxifen in reducing tumor volumes at 4 weeks. Additionally, the 75 mg/kg Z-endoxifen dose was additionally superior to letrozole. Prolonged letrozole exposure resulted in resistance at 25 weeks. In MCF7LR tumor-bearing mice, Z-endoxifen significantly reduced tumor volumes compared to tamoxifen, letrozole, and exemestane, with no significant differences compared to exemestane plus everolimus and fulvestrant. Additionally, compared to tamoxifen, Z-endoxifen markedly inhibited ER alpha target genes, Ki67 and Akt expression in vivo. Conclusion: In endocrine-sensitive and letrozole-resistant breast tumors, Z-endoxifen results in robust antitumor and antiestrogenic activity compared to tamoxifen and aromatase inhibitor monotherapy. These data support the ongoing development of Z-endoxifen.

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