Tamoxifen applications

The application of organometallic complexes of the other group 8 elements, iron and osmium, in anticancer drug design has until recently been almost exclusively focused on iron, with the ferrocenyl derivative of tamoxifen (ferrocifen) being the most prominent example (104). Organometallic osmium compounds have been little explored in this respect. 

The use of triphenylethylene SERMs as Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration, which is likely due to the involvement of proteins with the ability to bind these compounds. For instance, toremifene is able to reverse MDR and to sensitize human renal cancer cells to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular a 1-acid glycoprotein (AAG), which may limit its tissue availability (Braybrooke et al. 2000). In agreement with this, Chatterjee and Harris (1990) have shown that tamoxifen and 4-OH-tamoxifen were similarly potent in reversing MDR in Chinese hamster ovary (CHO) cells with acquired resistance to adriamycin. However, the addition of AAG (0.5 to 2 mg/ml, the range found in vivo) to cell cultures decreased the effect of tamoxifen on reversing MDR, and at the highest AAG concentration there was a complete reversal of the effects of... 

Another application of this chemistry is the asymmetric synthesis of the cyclopropane analog 25 of the breast cancer treatment agent tamoxifen 26 (Scheme 14.2) [53]. The Rh2(S-DOSP)4-catalyzed reaction of phenyldiazoacetate 3 with diarylethylene 23 at... 

Figure 1.4. Structure of clomiphene and tamoxifen, two non-steroidal synthetic anti-oestrogens that have found medical application...

Lee KH, Ward BA, Desta Z, Flockhart DA (2003) Jones DR (2003) Quantification of tamoxifen and three metaoblites in plasma by high-performance liquid chromatography with fluorescence detection application to a clinical trial. J Chromatogr B 791 245-253... 

Another drawback, challenging the routine applicability of some of these LC-MS and LC-MS/MS assays for measuring exposure to tamoxifen and its active metabolites is that for some assays no data have been provided concerning the validation process. Other methods have only been partially validated and have not or limitedly addressed matrix effects (ME) issues. 

Beer B et al (2010) Development and validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of tamoxifen, anastrozole, and letrozole in human plasma and its application to a clinical study. Anal Bioanal Chem 398 1791-1800... 

Zhu YB et al (2008) Optimizing high-performance liquid chromatography method with fluorescence detection for quantification of tamoxifen and two metabolites in human plasma application to a clinical study. J Pharm Biomed Anal 46 349-355... 

Jarman M, Leung OT, Leclercq G, Devleeschouwer N, Stoessel S, Coombes RC, Skilton RA (1986) Analogues of tamoxifen the role of the basic side-chain. Applications of a whole-cell oestrogen-receptor binding assay to N-oxides and quaternary salts. Anticancer Dmg Des 1 259-268... 

The stilbene derivative tamoxifen was the first synthetic nuclear receptor small-molecule modulator that demonstrated differential tissue effects. However, it has not found wide application as treatment for menopausal symptoms due to its stimulatory effects on the utems which cause a potential risk for endometrial cancer [53]. Despite this drawback tamoxifen is still used as a treatment for ER-positive breast cancer. 

Stiborova, M., L. Borek-Dohalska, P. Hodek, J. Mraz, and E. Frei (2002). New selective inhibitors of cytochromes P450 2B and their application to antimutagenesis of tamoxifen. Arch. Biochem. Biophys. 403, 41—49. 

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