Tamoxifen characterized

Second Generation Second generation SERMs were developed with the objective of obtaining ER-targeted pharmaceuticals that lacked the utero-trophic and carcinogenic effects of tamoxifen. The most well characterized second generation SERM is... 

Kedjouar B, de Medina P, Oulad-Abdelghani M, Payre B, Silvente-Poirot S, Favre G, Faye JC, Poirot M (2004) Molecular characterization of the microsomal tamoxifen binding site. J Biol Chem 279(32) 34048-34061... 

Hoffmann J, Bohlmann R, Heinrich N, Hofmeister H, Kroll J, Kunzer H, Lichtner RB, Nishino Y, Parczyk K, Sauer G, et al. (2004) Characterization of new estrogen receptor destabilizing compounds effects on estrogen-sensitive and tamoxifen-resistant breast cancer. J Natl Cancer Inst 96 210-218... 

Toremifen is a SERM considered a tamoxifen analog characterized by one chlorine atom and is approved for first-line treatment of metastasic breast cancer in postmenopausal women who have tumors that are either ER(+) or of unknown status. In a 3-year face-to-face study with tamoxifen, there were no significant differences between both drugs. The number and profile of adverse events are also similar. Experience with toremifen is limited and far from that accumulated with tamoxifen. 

L C. Raloxifene is a recently approved SERM. It is a partial estrogen agonist in breast tissue but was initially characterized as an antiestrogen. It, like the best-studied SERM, tamoxifen, has estrogen agonist properties in some tissues and estrogen antagonism properties in others. 

A logical extension of FI A with serial EC-LC-MS is to incorporate a separation technique to further characterize the products. Figure 8.2 is an example of precolumn EC oxidation of tamoxifen. With the EC cell at 500 mV, the total ion chromatogram (TIC) shows two primary peaks corresponding to starting material (tamoxifen) and, at an earlier retention time, an N-demethylated product. With the precolumn EC cell at 1000 mV (Fig. 8.3), additional peaks are evident, including possible aromatic... 

Johnson MD et al (2004) Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat 85 151-159... 

Sun D et al (2006) Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants. Breast Cancer Res 8 R50... 

Mazzarino M et al (2010) Mass spectrometric characterization of tamoxifene metabolites in human urine utilizing different scan parameters on liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 24 749-760... 

Memi oglu-Bilensoy, E., Vural, I., Renoir, J. M., Bochot, A., Duchene, D., and Hincal, A. A. (2005), Tamoxifen citrate loaded amphiphilic P-cyclodextrin nanoparticles In vitro characterization and cytotoxicity, J. Controlled Release, 104,489-496. 

Wolf, D.M. and Jordan, V.C. (1994) Characterization of tamoxifen stimulated MCF-7 tumor variants grown in athymic mice. Breast Cancer Research and Treatment, 31, 117-127. 

Nawata, H., Bronzert, D., and Lippman, M. E., Isolation and characterization of a tamoxifen-resistant cell line derived from MCF-7 human breast cancer cells. J. Biol. Chem. 256,5061-5021 (1981). 

Pharmacological management of breast cancer continues to make progress with advanced characterization techniques and the use of aromatase inhibitors and SERMs. Future generations of SERMs will need to be completely devoid of estrogenic activity to prevent the development of resistance, as is occurring with tamoxifen. 

Bhatia A, Singh B, Raza K, Wadhwa S, Katare OP. Tamoxifen-loaded lecithin organogel (LO) for topical application Development, optimization and characterization. Int J Pharm. 444(1-2) (2013) 47-59. 

Notley LM, Crewe KH, Taylor PJ, Lennard MS, Gillam EMJ (2005) Characterization of the human cytoehrome P450 forms involved in metabolism of tamoxifen to its a-hydroxy and 6t,4-dihydroxy derivatives. Chem Res Toxicol 18 1611-1618... 

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