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Boronic prodrug of endoxifen as an effective hormone therapy for breast cancer

  • Preclinical study
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Abstract

As a prodrug, tamoxifen is activated by the P450 enzyme CYP2D6 that is responsible for converting it to the active metabolites, 4-hydroxytamoxifen and endoxifen. Patients with genetic polymorphisms of CYP2D6 may not receive the full benefit of tamoxifen therapy. There is increasing evidence that poor metabolizer patients have lower plasma concentrations of endoxifen and suffer worse disease outcome, although some clinical studies reported no correlation between CYP2D6 polymorphism and tamoxifen therapy outcome. Endoxifen is currently undergoing clinical trials as a potentially improved and more potent SERM (Selective Estrogen Receptor Modulator) for endocrine therapy that is independent of CYP2D6 status in patients. However, direct administration of endoxifen may present the problem of low bioavailability due to its rapid first-pass metabolism via O-glucuronidation. We have designed and synthesized ZB483, a boronic prodrug of endoxifen suitable for oral administration with greatly enhanced bioavailability by increasing the concentration of endoxifen in mouse blood. Our study demonstrated that ZB483 potently inhibited growth of ER+ breast cancer cells in vitro and was efficiently converted to endoxifen in cell culture media by oxidative deboronation. This metabolic conversion is equally efficient in vivo as indicated in the pharmacokinetic study in mice. Moreover, when administered at the same dose, oral ZB483 afforded a 30- to 40-fold higher plasma level of endoxifen in mice than oral administration of endoxifen. The significantly enhanced bioavailability of endoxifen conferred by the boronic prodrug was further validated in an in vivo efficacy study. ZB483 was demonstrated to be more efficacious than endoxifen in inhibiting xenograft tumor growth in mice at equal dosage but more so at lower dosage. Together, these preclinical studies demonstrate that ZB483 is a promising endocrine therapy agent with markedly enhanced bioavailability in systemic circulation and superior efficacy compared to endoxifen.

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Acknowledgments

This study was supported by NIH grant 2G12MD007595 and 1U54GM104940.

Conflicts of interest

The authors declare no conflict of interest in this study.

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    Authors and Affiliations

    1. RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA, 70125, USA

      Changde Zhang, Qiu Zhong, Qiang Zhang, Shilong Zheng & Guangdi Wang

    2. Department of Chemistry, Xavier University of Louisiana, New Orleans, LA, 70125, USA

      Changde Zhang, Qiu Zhong, Qiang Zhang, Shilong Zheng & Guangdi Wang

    3. Department of Genetics and LSU Stanley Scott Cancer Center, LSU Health Sciences Center, New Orleans, LA, 70112, USA

      Lucio Miele

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    1. Changde Zhang
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    2. Qiu Zhong
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    4. Shilong Zheng
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    Correspondence to Shilong Zheng or Guangdi Wang.

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    Changde Zhang and Qiu Zhong have contributed equally to the work.

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    Zhang, C., Zhong, Q., Zhang, Q. et al. Boronic prodrug of endoxifen as an effective hormone therapy for breast cancer. Breast Cancer Res Treat 152, 283–291 (2015). https://doi.org/10.1007/s10549-015-3461-9

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    • DOI: https://doi.org/10.1007/s10549-015-3461-9

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