Relationship between genotypes Sult1a2 and Cyp2d6 and tamoxifen metabolism in breast cancer patients.

Tamoxifen is a pro-drug widely used in breast cancer patients to prevent tumor recurrence. Prior work has revealed a role of cytochrome and sulfotransferase enzymes in tamoxifen metabolism. In this descriptive study, correlations were examined between concentrations of tamoxifen metabolites and genotypes for CYP2D6, CYP3A4, CYP3A5, SULT1A1, SULT1A2 and SULT1E1 in 135 patients with estrogen receptor-positive breast cancer. Patients were genotyped using the Roche-AmpliChip® CYP450 Test, and Real-Time and conventional PCR-RFLP. Plasma tamoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, endoxifen and tamoxifen-N-oxide were isolated and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Significantly higher endoxifen levels were detected in patients with the wt/wt CYP2D6 compared to the v/v CYP2D6 genotype (p<0.001). No differences were detected in the remaining tamoxifen metabolites among CYP2D6 genotypes. Patients featuring the SULT1A2*2 and SULT1A2*3 alleles showed significantly higher plasma levels of 4-hydroxy-tamoxifen and endoxifen (p = 0.025 and p = 0.006, respectively), as likely substrates of the SULT1A2 enzyme. Our observations indicate that besides the CYP2D6 genotype leading to tamoxifen conversion to potent hydroxylated metabolites in a manner consistent with a gene-dose effect, SULT1A2 also seems to play a role in maintaining optimal levels of both 4-hydroxy-tamoxifen and endoxifen

Concentrations of tamoxifen and its metabolites (means (±SD), medians (in cursive) and ranges (in parentheses)) detected in patients with the <i>SULT1A1</i>, <i>SULT1A2</i> and <i>SULT1E1</i> genotypes.

<p>Concentrations of tamoxifen and its metabolites (means (±SD), medians (in cursive) and ranges (in parentheses)) detected in patients with the <i>SULT1A1</i>, <i>SULT1A2</i> and <i>SULT1E1</i> genotypes.</p

HPLC and MS parameters used to discriminate tamoxifen and its metabolites.

a<p>Multiple reaction monitoring.</p>b<p>Lower limit of quantification.</p

Concentrations of tamoxifen and its metabolites (means ± standard deviations, ng/mL) by <i>CYP2D6</i> and <i>SULT1A2</i> genotype subgroups established according to wt allele doses.

<p><i>Sample sizes: CYP2D6:</i> wt/wt = 80; wt/v = 30; v/v = 11//<i>SULT1A2:</i> wt/wt = 38; wt/v = 49; v/v = 34.</p

HPLC gradient parameters used to separate tamoxifen and its metabolites using a ZORBAX Eclipse XDB-C18 column (150 mm x 2.1 mm I.D., 3.5 µm) at 30°C.

a<p>Mobile phase A: 0.1% formic acid in water.</p>b<p>Mobile phase B: acetonitrile.</p

Concentrations of tamoxifen and its metabolites (means (±SD), medians (in cursive) and ranges (in parentheses)) detected in patients with the <i>CYP2D6</i>, <i>CYP3A4</i> and <i>CYP3A5</i> genotypes.

(+)<p>For the CYP2D6 genotypes:</p><p>“wt” includes all extensive metabolizer alleles (CYP2D6*1, CYP2D6*2, CYP2D6*35).</p><p>“wtxN” includes all ultraextensive metabolizer alleles (CYP2D6*1xN, CYP2D6*2xN).</p><p>“P” includes all null alleles (CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*6, CYP2D6*7, CYP2D6*8).</p><p>“I” includes all intermediate metabolizer alleles (CYP2D6*9, CYP2D6*10, CYP2D6*17, CYP2D6*41).</p

Adjusting the dose of tamoxifen in patients with early breast cancer and CYP2D6 poor metabolizer phenotype

CYP2D6 is a key enzyme in tamoxifen metabolism, transforming it into its main activemetabolite, endoxifen. Poor CYP2D6 metabolizers (PM) have lower endoxifen plasma concentrations and possibly benefit less from treatment with tamoxifen. We evaluated tamoxifen dose adjustment in CYP2D6 PM patients in order to obtain plasma concentrations of endoxifen comparable to patients with extensive CYP2D6 metabolism (EM). Comprehensive CYP2D6 genotyping and plasma tamoxifen metabolite concentrations were performed among 249 breast cancer patients in adjuvant treatment with tamoxifen. Tamoxifen dose was increased in PM patients to 40 mg and to 60 mg daily for a 4-month period each, repeating tamoxifen metabolite measurements on completion of each dose increase. We compared the endoxifen levels between EM and PM patients, and among the PM patients at each dose level of tamoxifen (20, 40 and 60 mg). Eleven PM patients (4.7%) were identified. The mean baseline endoxifen concentration in EM patients (11.30 ng/ml) was higher compared to the PM patients (2.33 ng/ml; p < 0.001). In relation to the 20 mg dose, increasing the tamoxifen dose to 40 and 60 mg in PM patients significantly raised the endoxifen concentration to 8.38 ng/ml (OR 3.59; p ¼ 0.013) and to 9.30 ng/ml (OR 3.99; p ¼ 0.007), respectively. These concentrations were comparable to those observed in EM patients receiving 20 mg of tamoxifen (p ¼ 0.13 and p ¼ 0.64, respectively). In CYP2D6 PM patients, increasing the standard tamoxifen dose two-fold or three-fold raisesendoxifen concentrations to levels similar to those of patients with EM phenotype.2.381 JCR (2014) Q2, 21/79 Obstetrics & gynecology; Q3, 129/211 OncologyUE

Punto de fuga. Punto de encuentro : aproximación interdisciplinar a las Vanguardias Artísticas de la segunda mitad del siglo XX

Resumen basado en el del proyecto. Premiado en la convocatoria: Premios para proyectos de innovación concluidos durante el curso 2007-2008, en los centros educativos no universitarios sostenidos con fondos públicos de la Comunidad Autónoma de Castilla-La Mancha (Orden 12-12-2008, de la Consejería de Educación y Ciencia de la Junta de Comunidades de Castilla-La Mancha. Resolución de 5-5-2009, de la Viceconsejería de Educación)El proyecto se desarrolla entre cinco centros: la Escuela de Arte de Guadalajarara, la Escuela de Hostelería y Turismo del IES Antonio Buero Vallejo de Guadalajara, el Conservatorio Provincial de Música de Guadalajara, el IES Profesor Domínguez Ortiz de Azuqueca de Henares y el Colegio Infantil y Primaria Castillo de Pioz. La idea central es la de abordar de forma interdisciplinar un tema común entre centros de distinta naturaleza armonizando el calendario de realización. Se buscan elementos integradores que permitan que el alumno se involucre activamente en un aprendizaje significativo con uno de los elementos clave en la educación, la motivación. Los objetivos son: fomentar la idea de que todas las áreas de conocimiento y creación humanas son producto de épocas y situaciones concretas englobadas en un todo; fomentar la participación activa en el proceso educativo; descubrir que el arte es algo vivo y que puede formar parte de la propia personalidad; fomentar el espíritu colectivo, la relevancia en el cumplimiento de los plazos y la valoración de la mirada del espectador sobre lo realizado; descubrir nuevos modos de comunicación y de relación; promover la reflexión anti-racista, anti-sexista, pacifista y solidaria. El tema elegido, la segunda mitad del siglo XX, especialmente las décadas de los 50, 60 y 70. Años de grandes transformaciones sociales y económicas en Europa. Su aproximación es multidisciplinar, desde la música, las artes plásticas, la literatura, la gastronomía, y el desarrollo del turismo como una industria potente que contribuirá además económicamente a sacar del ostracismo al pais.Castilla La ManchaConsejería de Educación, Ciencia y Cultura. Viceconsejería de Educación y Cultura. Servicio de Documentación; Bulevar del Río Alberche, s. n. - 1 Planta; 45071 Toledo; Tel. +34925286045; Fax +34925247410; [email protected]