Biomedical Engineering Reference
In-Depth Information
the light of recent findings —some of them made possible by the advent of new
powerful mass spectrometry techniques— suggesting that tamoxifen pharmaco-
logical activity and clinical outcomes do not rely on the parent drug only, but also
depends on the presence of several tamoxifen metabolites produced in patients via
complex metabolic pathways. A comprehensive review of mass spectrometry
methods for tamoxifen and its metabolites is therefore presented in the context of
the current growing interest for monitoring tamoxifen metabolites as a potentially
clinically useful tool to monitor tamoxifen treatment in breast cancer patients.
3.1
Clinical Rational for a TDM and Metabolites Pro fi ling
of Tamoxifen [ 145 ]
The non-steroidal selective estrogen receptor modulator (SERM), tamoxifen, was
the first molecularly targeted cancer therapy approved by the U.S. Food and Drug
Administration (FDA) since 1977 and 1998, respectively, for the treatment and pre-
vention of estrogen-sensitive breast cancer (BC) [ 146- 148 ] . Tamoxifen—the Z geo-
metric isomer of a triphenylethylene derivative—has been for more than three
decades the most widely used antihormonal therapy for premenopausal and post-
menopausal women with metastatic breast cancer, for adjuvant and neo-adjuvant
treatment of primary breast cancer and as a preventive agent for women at high risk
of developing the disease [ 149- 157 ] .
Selective estrogen receptor modulators, such as tamoxifen, display tissue-selec-
tive estrogen agonist or antagonist effects. In breast tissues, tamoxifen exerts an anti-
estrogenic activity mediated by the competitive inhibition of 17beta-estradiol (E2)
binding to estrogen receptors alpha and beta (ERa and ERb), resulting in the sup-
pression of ERa transcriptional activity and inhibition of estrogen-dependent growth
and proliferation of malignant breast epithelial cells [ 158- 161 ] . However, several
lines of evidence indicate that the overall anti-proliferative effects of tamoxifen
depend on the formation of the pharmacologically active metabolites 4-hydroxy-
tamoxifen and notably 4-hydroxy- N -desmethytamoxifen (endoxifen) which have up
to 100-fold greater affinity to ERs and 30 to 100-fold greater potency in suppressing
breast cancer cell proliferation as compared to the parent drug [ 10, 162- 164 ] .
Of these active metabolites, endoxifen is suggested to be the primary active
metabolite responsible for the majority of tamoxifen clinical efficacy, as endoxifen
plasma concentrations are about five to tenfold higher than those of 4-hydroxy-
tamoxifen [ 11, 165 ]. Endoxifen may have additional mechanisms of action than
4-hydroxy-tamoxifen by targeting Era for degradation by proteasome [ 166 ] and
through the promotion of ERa /ER b heterodimerization, blocking ERa transcrip-
tional activity [ 167 ] .
Tamoxifen could thus be considered a quasi-prodrug that requires metabolic bio-
activation to exert its effects. The metabolism of tamoxifen is complex and under-
goes extensive phase I and phase II transformation (Fig. 2 ). Various potentially
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