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Orally administered Endoxifen is a new therapeutic agent for breast cancer

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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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References

  1. E.B.C.T.C. Group (1998) Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 351:1451–1467

    Article  Google Scholar 

  2. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371–1388

    Article  CAS  PubMed  Google Scholar 

  3. Furr BJ, Jordan VC (1984) The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 25:127–205

    Article  CAS  PubMed  Google Scholar 

  4. Kinsinger LS, Harris R, Woolf SH, Sox HC, Lohr KN (2002) Chemoprevention of breast cancer: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 137:59–69

    Article  CAS  PubMed  Google Scholar 

  5. Costantino JP, Kuller LH, Ives DG, Fisher B, Dignam J (1997) Coronary heart disease mortality and adjuvant tamoxifen therapy. J Natl Cancer Inst 89:776–782

    Article  CAS  PubMed  Google Scholar 

  6. Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA (2005) CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97:30–39

    Article  CAS  PubMed  Google Scholar 

  7. Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, Desta Z, Flockhart DA, Skaar TC (2004) Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat 85:151–159

    Article  CAS  PubMed  Google Scholar 

  8. Holmes F, Liticker JD (2005) Pharmacogenomics of tamoxifen in a nutshell—and who broke the nutcracker? J Oncol Pract 1:155–159

    Article  PubMed  PubMed Central  Google Scholar 

  9. Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Weinshilboum RM, Fritcher EG, Nibbe AM, Desta Z, Nguyen A, Flockhart DA, Perez EA, Ingle JN (2007) The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat 101:113–121

    Article  CAS  PubMed  Google Scholar 

  10. Schroth W, Antoniadou L, Fritz P, Schwab M, Muerdter T, Zanger UM, Simon W, Eichelbaum M, Brauch H (2007) Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 25:5187–5193

    Article  CAS  PubMed  Google Scholar 

  11. Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes DF, Desta Z, Flockhart DA (2003) Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95:1758–1764

    Article  CAS  PubMed  Google Scholar 

  12. Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR (1988) Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res 48:589–601

    CAS  PubMed  Google Scholar 

  13. Grever MR, Schepartz SA, Chabner BA (1992) The National Cancer Institute: cancer drug discovery and development program. Semin Oncol 19:622–638

    CAS  PubMed  Google Scholar 

  14. Shoemaker RH (2006) The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer 6:813–823

    Article  CAS  PubMed  Google Scholar 

  15. Plowman J, Dykes DJ, Hollingstead M, Simpson-Herren L, Alley MC (1997) Human tumor xenograft models in NCI drug development. In Teicher B (ed) In Anticancer drug development guide: preclinical screening, clinical trials, and approval. Humana Press Inc., Totowa, NJ, chapter 6, pp 101–124

  16. Waud W, Dykes DJ, Hollingshead MG, Camalier RF, Steeg PS, Mayo JG (1999) Characterization of in vivo mammary and prostate tumor xenograft models for growth and response to clinical anticancer agents. In: Fiebig HH, Burger AM (eds) Relevance of tumor models for anticancer drug development. Contributions to oncology, vol 54. Kargel, Basel, pp 305–315

  17. Lazarus P, Blevins-Primeau AS, Zheng Y, Sun D (2009) Potential role of UGT pharmacogenetics in cancer treatment and prevention: focus on tamoxifen. Ann N Y Acad Sci 1155:99–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Daniel P, Gaskell SJ, Bishop H, Campbell C, Nicholson RI (1981) Determination of tamoxifen and biologically active metabolites in human breast tumours and plasma. Eur J Cancer Clin Oncol 17:1183–1189

    Article  CAS  PubMed  Google Scholar 

  19. Adam HK, Douglas EJ, Kemp JV (1979) The metabolism of tamoxifen in human. Biochem Pharmacol 28:145–147

    Article  CAS  PubMed  Google Scholar 

  20. Robinson SP, Langan-Fahey SM, Jordan VC (1989) Implications of tamoxifen metabolism in the athymic mouse for the study of antitumor effects upon human breast cancer xenografts. Eur J Cancer Clin Oncol 25:1769–1776

    Article  CAS  PubMed  Google Scholar 

  21. Wu X, Hawse JR, Subramaniam M, Goetz MP, Ingle JN, Spelsberg TC (2009) The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor α for degradation in breast cancer cells. Cancer Res 69(5):1722–1727

    Article  CAS  PubMed  Google Scholar 

  22. Borges S, Desta Z, Li L, Skaar TC, Ward BA, Nguyen A, Jin Y, Storniolo AM, Nikoloff DM, Wu L, Hillman G, Hayes DF, Stearns V, Flockhart DA (2006) Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther 80(1):61–74

    Article  CAS  PubMed  Google Scholar 

  23. Lash TL, Ahern TP, Cronin-Fenton D, Garne JP, Hamilton-Dutoit S, Kvistgaard ME, Rosenberg CL, Silliman RA, Sørensen HT (2008) Modification of tamoxifen response: what have we learned? J Clin Oncol 26(10):1764–1765

    Article  PubMed  Google Scholar 

  24. Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, Fritz P, Simon W, Suman VJ, Ames MM, Safgren SL, Kuffel MJ, Ulmer HU, Bolander J, Strick R, Beckmann MW, Koelbl H, Weinshilboum RM, Ingle JN, Eichelbaum M, Schwab M, Brauch H (2009) Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA 302(13):1429–1436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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  1. Jina Pharmaceuticals, Inc., 28100 N. Ashley Circle, Suite 103, Libertyville, IL, 60048, USA

    Ateeq Ahmad, Shoukath M. Ali, Moghis U. Ahmad, Saifuddin Sheikh & Imran Ahmad

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  1. Ateeq Ahmad
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  2. Shoukath M. Ali
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  3. Moghis U. Ahmad
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  4. Saifuddin Sheikh
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  5. Imran Ahmad
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Correspondence to Imran Ahmad.

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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

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