Abstract
Endoxifen is the key active metabolite of Tamoxifen, a widely used breast cancer drug. Orally administered Tamoxifen, is extensively metabolized by cytochrome P450 (CYP) enzymes, namely CYP3A4 and CYP2D6, into active metabolites, especially Endoxifen. Due to genetic polymorphism of CYP2D6, significant numbers of women metabolize Tamoxifen to varying degree and may not receive the optimal benefit from Tamoxifen treatment. We show that oral administration of Endoxifen achieved the optimally effective systemic levels reliably, which may eliminate variability associated with Tamoxifen metabolism that leads to unpredictability in efficacy. Furthermore, use of Endoxifen may avoid a potential serious drug interaction found between Tamoxifen and commonly used selective serotonin reuptake inhibitors, antidepressants. Endoxifen was active in inhibiting the growth of various breast tumor cell lines in NCI 60-Cell Line Screen. Orally administered Endoxifen is rapidly absorbed and systemically available when tested in female rats. The Endoxifen-treated rats showed 787% higher exposure (AUC0–∞) and 1,500% higher concentration (C max) levels of Endoxifen when compared with Tamoxifen. Oral Endoxifen administration once a day for 28 consecutive days at dosages 2, 4, and 8 mg/kg proved safe and resulted in progressive inhibition of the growth of the human mammary tumor xenografts in female mice. This is the first ever in vivo report on Endoxifen as a potentially new therapeutic agent for breast cancer.
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Acknowledgements
We thank the Developmental Therapeutics Program, NCI (http://dtp.cancer.gov/) for anti-cancer activity testing of Endoxifen in NCI 60-Cell Cell Line Screen. The efficacy evaluation of drugs in xenograft tumor model was conducted at AAALAC accredited Animal laboratories of Southern Research Institute, Birmingham, AL, 35255 USA. The toxicological studies in rats and mice were conducted in accordance with CPCSEA at Indian Institute of Toxicology, Pune, 411013 India. The LC-MS/MS analysis and pharmacokinetic evaluation of Endoxifen were carried out at Lambda Therapeutic Research Ltd., Ahmedabad, Gujarat, India.
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Ahmad, A., Ali, S.M., Ahmad, M.U. et al. Orally administered Endoxifen is a new therapeutic agent for breast cancer. Breast Cancer Res Treat 122, 579–584 (2010). https://doi.org/10.1007/s10549-009-0704-7
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DOI: https://doi.org/10.1007/s10549-009-0704-7