RESUMEN
Platinating agents are used in the treatment of many cancers, yet they can induce toxicities and resistance that limit their utility. Using previously published and additional world population panels of diverse ancestry totaling 608 lymphoblastoid cell lines (LCLs), we performed meta-analyses of over 3 million single-nucleotide polymorphisms (SNPs) for both carboplatin- and cisplatin-induced cytotoxicity. The most significant SNP in the carboplatin meta-analysis is located in an intron of NBAS (neuroblastoma amplified sequence; P=5.1 × 10(-7)). The most significant SNP in the cisplatin meta-analysis is upstream of KRT16P2 (P=5.8 × 10(-7)). We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Most of the variants that associate with platinum-induced cytotoxicity are polymorphic across multiple world populations; therefore, they could be tested in follow-up studies in diverse clinical populations. Seven genes previously implicated in platinating agent response, including BCL2 (B-cell CLL/lymphoma 2), GSTM1 (glutathione S-transferase mu 1), GSTT1, ERCC2 and ERCC6, were also implicated in our meta-analyses.
Asunto(s)
Compuestos Organoplatinos/uso terapéutico , Polimorfismo de Nucleótido Simple/efectos de los fármacos , Polimorfismo de Nucleótido Simple/genética , Carboplatino/efectos adversos , Carboplatino/uso terapéutico , Línea Celular , Cisplatino/efectos adversos , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos , Estudios de Seguimiento , Estudio de Asociación del Genoma Completo/métodos , Humanos , Proteínas de Neoplasias/genética , Compuestos Organoplatinos/efectos adversosRESUMEN
The use of cell-based models has emerged as a promising means to discover and validate pharmacologic phenotype-genotype relationships. The availability of large-scale genome studies in both human and model systems is now allowing us an unprecedented opportunity to understand how well cell-based models identify clinically relevant genetic variants associated with drug response and toxicity. Here we review these studies and the emerging translational information.
Asunto(s)
Descubrimiento de Drogas/métodos , Farmacogenética/métodos , Investigación Biomédica Traslacional/métodos , Animales , Línea Celular Tumoral , Descubrimiento de Drogas/tendencias , Genómica/métodos , Genómica/tendencias , Humanos , Farmacogenética/tendencias , Polimorfismo de Nucleótido Simple/genética , Investigación Biomédica Traslacional/tendenciasRESUMEN
In intestinal epithelia, cholera and related toxins elicit a cAMP-dependent chloride secretory response fundamental to the pathogenesis of toxigenic diarrhea. We recently proposed that specificity of cholera toxin (CT) action in model intestinal epithelia may depend on the toxin's cell surface receptor ganglioside G(M1). Binding G(M1) enabled the toxin to elicit a response, but forcing the toxin to enter the cell by binding the closely related ganglioside G(D1a) rendered the toxin inactive. The specificity of ganglioside function correlated with the ability of G(M1) to partition CT into detergent-insoluble glycosphingolipid-rich membranes (DIGs). To test the biological plausibility of these hypotheses, we examined native human intestinal epithelia. We show that human small intestinal epithelia contain DIGs that distinguish between toxin bound to G(M1) and G(D1a), thus providing a possible mechanism for enterotoxicity associated with CT. We find direct evidence for the presence of caveolin-1 in DIGs from human intestinal epithelia but find that these membranes are heterogeneous and that caveolin-1 is not a structural component of apical membrane DIGs that contain CT.
