RESUMO
OBJECTIVES: We studied the relation between the polymorphism of P-glycoprotein (P-gp) and of breast cancer resistance protein (BCRP), encoded by ABCB1 and ABCG2 genes, respectively, and the pharmacokinetic variability and clinical response during the treatment with sorafenib of hepatocellular carcinoma. METHODS: At the Paul Brousse Hospital in Villejuif, France, 47 consecutive patients with advanced HCC treated with a single agent sorafenib, were enrolled. Sorafenib exposure was measured by its plasma concentration 3 h after oral administration of 400 mg (bid) by liquid chromatography. All enrolled patients were genotyped for ABCB1 (rs2032582; rs1045642) and ABCG2 (rs2231137; rs2231142; rs2622604) by blood genomic DNA extraction and Mass ARRAY genotyping. The clinical response was evaluated after 3months of treatment according to the RECIST criteria. KEY FINDINGS: Significant associations between sorafenib exposure and the studied polymorphisms were observed for ABCB1 3435C>T, ABCG2 34G>A, ABCG2 1143C>T and ABCG2 421C>A, but not for ABCB1 2677G>TA SNP. In heterozygous patients for ABCB1 3435 C>T, ABCG2 34 G>A and ABCG2 1143 C>T polymorphisms were significantly associated with the lowest sorafenib plasma levels. Those patients presented a tendency to have the best clinical evolution. CONCLUSION: Heterozygous forms of the studied polymorphisms could be associated with a better therapeutic response.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/uso terapêutico , Neoplasias da Mama/genética , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Proteínas de Neoplasias/genética , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacocinética , Neoplasias da Mama/tratamento farmacológico , DNA/genética , Monitoramento de Medicamentos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/farmacocinética , Niacinamida/uso terapêutico , Compostos de Fenilureia/farmacocinética , Polimorfismo Genético/genética , Polimorfismo de Nucleotídeo Único/genética , Inibidores de Proteínas Quinases/farmacocinética , Sorafenibe , Resultado do TratamentoRESUMO
Chromophobe renal cell carcinoma (chRCC) is a common subtype of renal cell carcinoma (RCC), occurring in 6-11% of renal carcinoma patients. Limited clinical trial data have shown minimal activity with cytokines and chemotherapy, although small-molecule inhibitors of the vascular endothelial growth factor and platelet-derived growth factor pathways such as sunitinib and sorafenib, which are associated with significant clinical activity in clear-cell RCC (ccRCC), have been associated with a 25% response rate in chRCC. The mammalian target of rapamycin kinase inhibitor temsirolimus demonstrates good clinical activity in ccRCC patients with poor prognosis, with further data suggesting it is an effective treatment for all RCC tumour histologies. This report describes the case of a patient with chRCC who experienced rapid improvement in his general condition and stable disease on treatment with temsirolimus, following disease progression on interferon alfa and sorafenib treatment. This case report suggests that temsirolimus is an effective and appropriate treatment for this RCC tumour subtype.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Terapia de Salvação , Sirolimo/análogos & derivados , Benzenossulfonatos/administração & dosagem , Carcinoma de Células Renais/secundário , Humanos , Interferons/administração & dosagem , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/administração & dosagem , Sirolimo/uso terapêutico , Sorafenibe , Resultado do TratamentoRESUMO
The development of targeted molecules in renal carcinogenesis changed the therapeutic approaches of treatment for metastatic clear cell renal cell carcinoma. Four available drugs are currently available, i.e. bevacizumab, sunitinib, sorafenib and temsirolimus, but other molecules and combined therapy are under investigation. In this review we assess published reports of these targeted therapies and discuss the novel promising molecules targeting vascular endothelial growth factor and its receptors, the mammalian target of rapamycin and epithelial growth factor cascade.