Identification of molecular pathways involved in oxaliplatin-associated sinusoidal dilatation.
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos Organoplatínicos
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Doenças Vasculares
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Transdução de Sinais
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Perfilação da Expressão Gênica
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Fígado
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Antineoplásicos
Tipo de estudo:
Diagnostic_studies
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Observational_studies
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Risk_factors_studies
Limite:
Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
J Hepatol
Ano de publicação:
2012
Tipo de documento:
Article