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Identification of molecular pathways involved in oxaliplatin-associated sinusoidal dilatation.
Agostini, Julie; Benoist, Stéphane; Seman, Marie; Julié, Catherine; Imbeaud, Sandrine; Letourneur, Franck; Cagnard, Nicolas; Rougier, Philippe; Brouquet, Antoine; Zucman-Rossi, Jessica; Laurent-Puig, Pierre.
Afiliação
  • Agostini J; Paris Descartes University, Paris Sorbonne Cité, INSERM UMR-S775, Paris, France.
J Hepatol ; 56(4): 869-76, 2012 Apr.
Article em En | MEDLINE | ID: mdl-22200551
BACKGROUND & AIMS: Oxaliplatin-based chemotherapy for colorectal liver metastases (CRLM) can result in vascular liver lesions such as sinusoidal dilatations. Physiopathology remains unclear and variability between patients suggests that there is individual susceptibility. A better understanding of the molecular mechanisms of oxaliplatin liver toxicity may allow the identification of biomarkers and adaptation of chemotherapy delivery. METHODS: Between 1998 and 2009, 83 non-tumor frozen liver samples were obtained from patients operated on for CRLM after an exclusive oxaliplatin-based chemotherapy. Gene-expression profiles were first analyzed by microarray on a selected population of 19 patients: 9 patients with severe sinusoidal dilatation after a short period of chemotherapy and 10 patients without any sinusoidal dilatation after a long period of chemotherapy. These were compared with a control group of 5 patients without any chemotherapy and lesions. Twenty-two differentially-expressed (at least 1.5-fold difference in expression) genes were selected. These were validated using microfluidic quantitative RT-PCR in an independent set of 58 patients (28 with sinusoidal dilatation and 30 without sinusoidal dilatation). RESULTS: Among the 22 selected genes, 12 were validated as being up-regulated in samples from patients with sinusoidal dilatation compared to patients without sinusoidal dilatation. Genes involved in angiogenesis (VEGFD, THY-1, GPNMB) and cellular adhesion (VWF, CDH13, THBS2), and extracellular matrix components (COL1A1, COL4A1, SLCO1A2) were over-represented in patients with sinusoidal dilatation. CONCLUSIONS: This molecular signature confirms the involvement of angiogenesis and coagulation in sinusoidal injuries induced by oxaliplatin and reinforces a potential protective role of bevacizumab and aspirin, as suggested in retrospective clinical studies.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Compostos Organoplatínicos / Doenças Vasculares / Transdução de Sinais / Perfilação da Expressão Gênica / Fígado / Antineoplásicos Tipo de estudo: Diagnostic_studies / Observational_studies / Risk_factors_studies Limite: Female / Humans / Male / Middle aged Idioma: En Revista: J Hepatol Ano de publicação: 2012 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Compostos Organoplatínicos / Doenças Vasculares / Transdução de Sinais / Perfilação da Expressão Gênica / Fígado / Antineoplásicos Tipo de estudo: Diagnostic_studies / Observational_studies / Risk_factors_studies Limite: Female / Humans / Male / Middle aged Idioma: En Revista: J Hepatol Ano de publicação: 2012 Tipo de documento: Article