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1.
J Natl Compr Canc Netw ; 21(1): 33-41.e16, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36634607

RESUMEN

BACKGROUND: The potential gonadotoxicity of anti-HER2 agents remains largely unknown, and limited, conflicting evidence exists for taxanes. Antimüllerian hormone (AMH) is an established biomarker of ovarian reserve that may aid in quantifying anticancer treatment-induced gonadotoxicity. PATIENTS AND METHODS: The present biomarker analysis of the randomized phase III neoadjuvant NeoALTTO trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early breast cancer with available frozen serum samples at baseline (ie, before anticancer treatments), at week 2 (ie, the "biological window" of anti-HER2 therapy alone), and/or at the time of surgery (ie, after completing paclitaxel + anti-HER2 therapy, before starting adjuvant chemotherapy). RESULTS: The present analysis included 130 patients with a median age of 38 years (interquartile ratio [IQR], age 33-42 years). AMH values at the 3 time points differed significantly (P<.001). At baseline, median AMH levels were 1.29 ng/mL (IQR, 0.56-2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median, 1.10 ng/mL; IQR, 0.45-2.09 ng/mL; P<.001). At surgery, a larger significant decline in AMH levels was observed (median, 0.01 ng/mL; IQR, 0.01-0.03 ng/mL; P<.001). Although the type of anti-HER2 treatment (trastuzumab and/or lapatinib) did not seem to impact the results, age and pretreatment ovarian reserve had a major influence on treatment-induced gonadotoxicity risk. CONCLUSIONS: This NeoALTTO biomarker analysis showed that anti-HER2 therapies alone had limited gonadotoxicity but that the addition of weekly paclitaxel resulted in marked AMH decline with possible negative implications for subsequent ovarian function and fertility.


Asunto(s)
Neoplasias de la Mama , Reserva Ovárica , Humanos , Femenino , Adulto , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Paclitaxel/efectos adversos , Lapatinib/uso terapéutico , Biomarcadores
2.
Eur J Cancer ; 118: 169-177, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31377477

RESUMEN

BACKGROUND: Lapatinib (L) plus trastuzumab (T) with weekly paclitaxel significantly increased the pathologic complete response (pCR) rate compared with the anti-human epidermal growth factor receptor 2 (HER2) agent alone plus paclitaxel. The event-free survival (EFS) and overall survival (OS) by the treatment arms L + T vs. T and L vs. T and the relationship between pCR and EFS/OS both in the whole study population and according to hormone receptor-negative and hormone receptor-positive cohorts after a median follow-up of 6.7 years were assessed. PATIENTS AND METHODS: Four hundred fifty-five patients with HER2-positive early breast cancer randomly received L 1500 mg/day (n = 154), T (common dose, n = 149) or L 1000 mg/day plus T (n = 152) for 6 weeks, followed by the assigned anti-HER2 treatment combined with paclitaxel weekly × 12. After surgery, patients received 3 cycles of fluorouracil, epirubicin and cyclophosphamide. The primary end-point was pCR (ypT0/is; for current analysis, it is ypT0/is ypN0), and the secondary end-points were EFS and OS. RESULTS: Six-year EFS rates were 67%, 67% and 74% with L, T and L + T, respectively (L vs T: hazard ratio [HR], 0.98 [95% confidence interval {CI}, 0.64-1.51; P = .93]; L + T vs T: HR, 0.81 [95% CI, 0.52-1.26; P = .35]). Six-Year OS rates were 82%, 79% and 85% for L, T and L + T, respectively (L vs T: HR, 0.85 [95% CI, 0.49-1.46; P = .56]; L + T vs T: HR, 0.72 [95% CI, 0.41-1.27; P = .26]). In landmark analyses, patients with a pCR had a significantly higher 6-year EFS (77% and 65%) and OS (89% and 77%) compared with those without a pCR for both overall and the hormone receptor-negative cohort. CONCLUSION: Achieving a pCR is important in HER2-positive disease and translates into better long-term outcome with regard to EFS and OS.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Lapatinib/uso terapéutico , Terapia Neoadyuvante , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Trastuzumab/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Progresión de la Enfermedad , Femenino , Humanos , Lapatinib/efectos adversos , Mastectomía , Terapia Neoadyuvante/efectos adversos , Terapia Neoadyuvante/mortalidad , Paclitaxel/uso terapéutico , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Receptor ErbB-2/metabolismo , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Trastuzumab/efectos adversos
3.
J Lipid Res ; 46(6): 1133-49, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15741651

RESUMEN

Mitochondrial cytopathy has been associated with modifications of lipid metabolism in various situations, such as the acquisition of an abnormal adipocyte phenotype observed in multiple symmetrical lipomatosis or triglyceride (TG) accumulation in muscles associated with the myoclonic epilepsy with ragged red fibers syndrome. However, the molecular signaling leading to fat metabolism dysregulation in cells with impaired mitochondrial activity is still poorly understood. Here, we found that preadipocytes incubated with inhibitors of mitochondrial respiration such as antimycin A (AA) accumulate TG vesicles but do not acquire specific markers of adipocytes. Although the uptake of TG precursors is not stimulated in 3T3-L1 cells with impaired mitochondrial activity, we found a strong stimulation of glucose uptake in AA-treated cells mediated by calcium and phosphatidylinositol 3-kinase/Akt1/glycogen synthase kinase 3beta, a pathway known to trigger the translocation of glucose transporter 4 to the plasma membrane in response to insulin. TG accumulation in AA-treated cells is mediated by a reduced peroxisome proliferator-activated receptor gamma activity that downregulates muscle carnitine palmitoyl transferase-1 expression and fatty acid beta-oxidation, and by a direct conversion of glucose into TGs accompanied by the activation of carbohydrate-responsive element binding protein, a lipogenic transcription factor. Taken together, these results could explain how mitochondrial impairment leads to the multivesicular phenotype found in some mitochondria-originating diseases associated with a dysfunction in fat metabolism.


Asunto(s)
Ácidos Grasos/metabolismo , Glucosa/metabolismo , Mitocondrias/patología , Oxígeno/metabolismo , Triglicéridos/metabolismo , Células 3T3-L1 , Adipocitos/citología , Animales , Western Blotting , Calcio/metabolismo , Metabolismo de los Hidratos de Carbono , Carnitina O-Palmitoiltransferasa/biosíntesis , Diferenciación Celular , Membrana Celular/metabolismo , Células Cultivadas , ADN/metabolismo , Regulación hacia Abajo , Inhibidores Enzimáticos/farmacología , Glucosa/farmacocinética , Transportador de Glucosa de Tipo 4 , Metabolismo de los Lípidos , Luciferasas/metabolismo , Ratones , Microscopía Confocal , Microscopía Fluorescente , Mitocondrias/metabolismo , Modelos Biológicos , Proteínas de Transporte de Monosacáridos/metabolismo , Proteínas Musculares/metabolismo , Músculos/enzimología , PPAR gamma/metabolismo , Fenotipo , Fosfatidilinositol 3-Quinasas/metabolismo , Unión Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Transporte de Proteínas , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , ARN Mensajero/metabolismo , Receptor alfa X Retinoide/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Transfección
4.
Exp Cell Res ; 295(2): 340-9, 2004 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-15093734

RESUMEN

Hypoxia inducible factor-1 (HIF-1) is the main transcriptional factor activated by hypoxia. Besides the well-described role assigned to HIF-1 in the adaptation of cells to hypoxia, different recent data describe a possible role for HIF-1 in the modulation of apoptosis. However, this precise role is not yet clearly understood. In this study, chemical and physiological hypoxia, which were shown to induce HIF-1alpha stabilization and HIF-1 activation, were shown to inhibit apoptosis induced in HepG2 cells by two different pro-apoptotic conditions, serum deprivation- and t-BHP-induced oxidative stress. Indeed, hypoxia reduced DNA fragmentation, caspase activation, and PARP cleavage induced by these two pro-apoptotic conditions. These results are very interesting because it is a clear demonstration that hypoxia and chemical hypoxia have a direct protective effect on apoptotic cell death induced by two different stimuli. This observation is an important data in understanding how tumor growth can occur in challenging environmental conditions.


Asunto(s)
Apoptosis/fisiología , Hipoxia de la Célula/fisiología , Cobalto/toxicidad , Proteínas de Unión al ADN/metabolismo , Proteínas Nucleares/metabolismo , terc-Butilhidroperóxido/farmacología , Apoptosis/efectos de los fármacos , Western Blotting , Carcinoma Hepatocelular , Caspasas/metabolismo , Línea Celular Tumoral , Medio de Cultivo Libre de Suero , Activación Enzimática , Genes Reporteros , Humanos , Factor 1 Inducible por Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neoplasias Hepáticas , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Reacción en Cadena de la Polimerasa , Factores de Transcripción/fisiología
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