Simulation with cells <i>in vitro</i> of tamoxifen treatment in premenopausal breast cancer patients with different <scp>CYP2D</scp>6 genotypes

Maximov, Philipp Y.; McDaniel, Russell E.; Fernandes, Daphne J.; Korostyshevskiy, Valeriy R.; Bhatta, Puspanjali; Mürdter, Thomas E.; Flockhart, David A.; Jordan, V. Craig

doi:10.1111/bph.12864

Cited by 30 publications

(28 citation statements)

References 38 publications

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“…The antiestrogenic activities of tamoxifen and metabolites can be different when investigated in different cell lines, or in the presence of estrogen concentrations [31, 32]. However, the in vitro experiments were conducted to obtain the relative antiestrogenic activities of tamoxifen and three metabolites.…”

Section: Discussionmentioning

confidence: 99%

An Antiestrogenic Activity Score for tamoxifen and its metabolites is associated with breast cancer outcome

Schultink

Alexi

Werkhoven

et al. 2016

Breast Cancer Res Treat

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Purpose Endoxifen concentrations have been associated with breast cancer recurrence in tamoxifen-treated patients. However, tamoxifen itself and other metabolites also show antiestrogenic anti-tumor activity. Therefore, the aim of this study was to develop a comprehensive Antiestrogenic Activity Score (AAS), which accounts for concentration and antiestrogenic activity of tamoxifen and three metabolites. An association between the AAS and recurrence-free survival was investigated and compared to a previously published threshold for endoxifen concentrations of 5.97 ng/mL. Patients and methods The antiestrogenic activities of tamoxifen, (Z)-endoxifen, (Z)-4-hydroxytamoxifen, and N-desmethyltamoxifen were determined in a cell proliferation assay. The AAS was determined by calculating the sum of each metabolite concentration multiplied by an IC50 ratio, relative to tamoxifen. The AAS was calculated for 1370 patients with estrogen receptor alpha (ERα)-positive breast cancer. An association between AAS and recurrence was investigated using Cox regression and compared with the 5.97 ng/mL endoxifen threshold using concordance indices. Results An AAS threshold of 1798 was associated with recurrence-free survival, hazard ratio (HR) 0.67 (95% confidence interval (CI) 0.47–0.96), bias corrected after bootstrap HR 0.69 (95% CI 0.48–0.99). The concordance indices for AAS and endoxifen did not significantly differ; however, using the AAS threshold instead of endoxifen led to different dose recommendations for 5.2% of the patients. Conclusions Endoxifen concentrations can serve as a proxy for the antiestrogenic effect of tamoxifen and metabolites. However, for the aggregate effect of tamoxifen and three metabolites, defined by an integrative algorithm, a trend towards improving treatment is seen and moreover, is significantly associated with breast cancer recurrence.

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Section: Discussionmentioning

confidence: 99%

An Antiestrogenic Activity Score for tamoxifen and its metabolites is associated with breast cancer outcome

Schultink

Alexi

Werkhoven

et al. 2016

Breast Cancer Res Treat

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“…13) to view these data based on the results previously discussed in the section describing the drift in cell populations in vitro if estrogen induced apoptosis is blocked by an inhibitor of cSrc. The principle of improving the antiestrogenic mixture of metabolites in both a premenopausal and postmenopausal patient environment has recently been modeled in vitro (194, 195). These studies represent the immediate effects of tamoxifen and metabolites of estrogen stimulated growth and gene regulation.…”

Section: Summary and Future Clinical Perspectivementioning

confidence: 99%

The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer

Jordan¹

2014

Endocrine-Related Cancer

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121

100

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The successful use of high dose synthetic estrogens to treat post-menopausal metastatic breast cancer, is the first effective “chemical therapy” proven in clinical trial to treat any cancer. This review documents the clinical use of estrogen for breast cancer treatment or estrogen replacement therapy (ERT) for postmenopausal hysterectomized women which can either result in breast cancer cell growth or breast cancer regression. This has remained a paradox since the 1950s until the discovery of the new biology of estrogen induced apoptosis at the end of the 20th century. The key to triggering apoptosis with estrogen is the selection of breast cancer cell populations that are resistant to long term estrogen deprivation. However, through trial and error estrogen independent growth occurs. At the cellular level, estrogen induced apoptosis is dependent upon the presence of the estrogen receptor (ER) which can be blocked by non-steroidal or steroidal anti-estrogens. The shape of an estrogenic ligand programs the conformation of the ER complex which in turn can modulate estrogen induced apoptosis: class I planar estrogens (eg: estradiol) trigger apoptosis after 24 hours whereas class II angular estrogens (eg: bisphenol triphenylethylene) delay the process until after 72 hours. This contrasts with paclitaxel that causes G2 blockade with immediate apoptosis. The process is complete within 24 hours. Estrogen induced apoptosis is modulated by glucocorticoids and cSrc inhibitors but the target mechanism for estrogen action is genomic and not through a non-genomic pathway. The process is step wise through the creation of endoplasmic reticulum stress and, inflammatory responses that then initiate an unfolded protein response. This in turn initiates apoptosis through the intrinsic pathway (mitochondrial) with subsequent recruitment of the extrinsic pathway (death receptor) to complete the process. The symmetry of the clinical and laboratory studies now permits the creation of rules for the future clinical application of ERT or phytoestrogen supplements: a five year gap is necessary after menopause to permit the selection of estrogen deprived breast cancer cell populations to become vulnerable to apoptotic cell death. Earlier treatment with estrogen around the menopause encourages ER positive tumor cell growth, as the cells are still dependent on estrogen to maintain replication within the expanding population. An awareness of the evidence that the molecular events associated with estrogen induced apoptosis can be orchestrated in the laboratory in estrogen deprived breast cancers, now support the clinical findings for the treatment of metastatic breast cancer following estrogen deprivation, decreases in mortality following long term antihormonal adjuvant therapy, and the results of ERT and ERT plus progestin in the Women’s Health Initiative for women over the age of 60. Principles have emerged to understand and apply physiologic estrogen therapy appropriately by targeting the correct patient populations.

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“…27,28) Using immunohistochemistry, we found that CYP2D6 protein was localized in the enterocytes and lamina propria of the small intestine of Japanese individuals. Although CYP2D6 mRNA levels were lower than the CYP3A4 mRNA levels in the samples, we did find that CYP2D6 mRNA was expressed in the small intestine of Japanese individuals.…”

Section: Discussionmentioning

confidence: 94%

Evaluation of CYP2D6 Protein Expression and Activity in the Small Intestine to Determine Its Metabolic Capability in the Japanese Population

Kawakami

Takenoshita-Nakaya

Takeba

et al. 2017

Biological & Pharmaceutical Bulletin

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CYP2D6 plays an important role in the metabolism of many drugs such as opioids and antidepressants. Polymorphisms of the CYP2D6 gene are widely observed in the Japanese population, and can affect the firstpass metabolism of orally administered drugs. Several CYP enzymes have been identified in the small intestine of Caucasians, but intestinal CYP enzymes have not been reported in the Japanese population, except for CYP3A4 and CYP2C19. In this study, we evaluated the CYP2D6 metabolic capacity by measurement of CYP2D6 mRNA and protein levels and activity in the small intestine of Japanese individuals. Normal jejunal tissues were obtained from 31 patients who had undergone pancreaticoduodenectomy, and the CYP2D6*10 variant was identified in these tissues. CYP2D6 mRNA and CYP2D6 protein levels were analyzed using realtime RT-PCR and Western blotting, respectively. Bufuralol 1′-hydroxylation, a marker of CYP2D6 activity, was analyzed using HPLC. Frequencies of the CYP2D6*1/*1, *1/*10, and *10/*10 genotypes in the jejunal tissue were 29.0% (n 9), 35.5% (n 11), and 35.5% (n 11), respectively. CYP2D6 protein and activity levels did not differ significantly between the genotypes. A positive correlation was found between CYP2D6 protein and activity levels. Furthermore, CYP2D6 protein levels and activity in the small intestine were significantly lower than those in the liver. These findings suggest that the metabolic capacity of CYP2D6 in the small intestine of the Japanese population has a relatively small effect on drug metabolism. Key words CYP 2D6; small intestine; Japanese; polymorphism; bufuralol CYP enzymes are present in most tissues in the body, but are most abundant in the liver. There, they play a pivotal role in the metabolism of endogenous substrates and of exogenous compounds such as xenobiotics.1) Their presence in extrahepatic tissues, such as the esophagus, stomach, and small intestine, 2-4) also contributes to drug metabolism. 5-7) Paine et al. reported a significant contribution of CYP enzymes in the small intestine to the first-pass metabolism of midazolam, specifically by intestinal CYP3A4.7) Expressions of CYP3A, CYP2C9, CYP2C19, CYP2D6, CYP2J2, and CYP4F proteins have been demonstrated in the small intestine of Caucasians. 4,8) Of these, CYP2D6 plays a particularly important role in drug metabolism. Although CYP2D6 accounts for only 2% of the total CYP protein in the liver, it is a very important isoform because it metabolizes approximately 20-25% of commonly used drugs, including codeine, tramadol, and tamoxifen. 9) However, CYP2D6 expression and activity have not yet been characterized in the small intestine of the Japanese population.CYP2D6 gene polymorphisms are produced from over 109 allelic variants.10) The phenotypes resulting from these polymorphisms are associated with abolished, decreased, and increased enzyme activity, and the resulting phenotypes can be classified as a poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM), or ultra-rapid metabolizer (UM), based ...

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Simulation with cells in vitro of tamoxifen treatment in premenopausal breast cancer patients with different CYP2D6 genotypes

Cited by 30 publications

References 38 publications

An Antiestrogenic Activity Score for tamoxifen and its metabolites is associated with breast cancer outcome

An Antiestrogenic Activity Score for tamoxifen and its metabolites is associated with breast cancer outcome

The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer

Evaluation of CYP2D6 Protein Expression and Activity in the Small Intestine to Determine Its Metabolic Capability in the Japanese Population

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