Publication: Nuevas estrategias de espectrometría de masas para la obtención y cuantificación de bioimágenes de platino y determinación de proteínas ligadas a fármacos platinados en estudios de nefrotoxicidad
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2018-08-23
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Universidad Complutense de Madrid
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Abstract
Desde que en los años 70 se descubriese fortuitamente la actividad antineoplásica del cisplatino, éste ha sido empleado con gran éxito en el tratamiento de numerosos tumores, siendo hoy en día el fármaco más empleado en quimioterapia. Sin embargo, en su aplicación surgen diversos inconvenientes como la aparición de resistencias intrínsecas o desarrolladas al fármaco, así como la aparición de diferentes efectos secundarios. Entre estos últimos destaca la nefrotoxicidad inducida en el tratamiento con cisplatino, la cual limita la dosis administrable del fármaco. Por ello, otros fármacos con base de Pt de segunda y tercera generación han sido desarrollados con el fin de mejorar sus propiedades. Sin embargo, actualmente el cisplatino sigue siendo ineludible en las terapias contra el cáncer. Es bien sabido que la actividad antineoplásica del cisplatino se debe a su interacción con su diana farmacológica principal, el ADN, al cual se coordina formando diferentes aductos cisplatino-ADN que provocan una disrupción en la doble hélice y provocando así la muerte celular por apoptosis. Sin embargo, debido a la gran reactividad que presenta el cisplatino, éste puede unirse a otras biomoléculas diferentes a su diana farmacológica como son las proteínas. Esta interacción es de gran importancia, ya que juega un papel fundamental en su complicado mecanismo de toxicidad y en la aparición de resistencia al fármaco y efectos secundarios. Por ello, el estudio de dichas interacciones presenta gran interés, ya que puede arrojar cierta luz a la comprensión de los mecanismos de aparición de nefrotoxicidad, lo cual ayudaría en el diseño de terapias mejoradas y fármacos nefroprotectores. Por todo ello, el objetivo principal de esta tesis doctoral ha consistido en el desarrollo de estrategias bioanalíticas basadas en espectrometría de masas atómica y molecular, técnicas de separación electroforéticas y nuevos métodos de preparación de la muestra para la determinación de proteínas ligadas a fármacos con base de Pt en muestras biológicas relacionadas con el fracaso renal, así como para la obtención de mapas de distribución de Pt en tejidos afectados...
Since the anticancer activity of cisplatin was discovered by chance in the 1970s, it has been successfully used in the treatment of numerous tumors, and is nowadays the most widely used drug in chemotherapy. However, several problems arise in its application, such as the appearance of intrinsic or developed resistance to the drug, as well as the appearance of different side effects. Among the latter, nephrotoxicity induced in cisplatin treatment, which limits the administrable dose of the drug, is highlighted. Therefore, other drugs with second and third generation Pt base have been developed in order to improve their properties. However, cisplatin is currently unavoidable in anticancer therapies. It is well known that the antineoplasic activity of cisplatin is due to its interaction with its main pharmacological target, DNA, which is coordinated by forming different cisplatin-DNA adducts that cause disruption in the double helix and thus causing cell death by apoptosis. However, due to the high reactivity of cisplatin, it can bind to other biomolecules different than its pharmacological target such as proteins. This interaction is of great importance as it plays a key role in its complicated mechanism of toxicity and in the appearance of drug resistance and side effects. Therefore, the study of these interactions is of great interest, as it may shed some light on the understanding of the mechanisms of nephrotoxicity, which would help in the design of improved therapies and nephroprotective drugs...
Since the anticancer activity of cisplatin was discovered by chance in the 1970s, it has been successfully used in the treatment of numerous tumors, and is nowadays the most widely used drug in chemotherapy. However, several problems arise in its application, such as the appearance of intrinsic or developed resistance to the drug, as well as the appearance of different side effects. Among the latter, nephrotoxicity induced in cisplatin treatment, which limits the administrable dose of the drug, is highlighted. Therefore, other drugs with second and third generation Pt base have been developed in order to improve their properties. However, cisplatin is currently unavoidable in anticancer therapies. It is well known that the antineoplasic activity of cisplatin is due to its interaction with its main pharmacological target, DNA, which is coordinated by forming different cisplatin-DNA adducts that cause disruption in the double helix and thus causing cell death by apoptosis. However, due to the high reactivity of cisplatin, it can bind to other biomolecules different than its pharmacological target such as proteins. This interaction is of great importance as it plays a key role in its complicated mechanism of toxicity and in the appearance of drug resistance and side effects. Therefore, the study of these interactions is of great interest, as it may shed some light on the understanding of the mechanisms of nephrotoxicity, which would help in the design of improved therapies and nephroprotective drugs...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Química Analítica, leída el 02-06-2017