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La inhibición de la transcripción por los enlaces cruzados platino-ADN en células de mamíferos vivos
Wee Han Ang1, MyatNoeZin Myint, Stephen J Lippard
1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Journal of the American Chemical Society
|May 7, 2010
Resumen
Los enlaces cruzados platino-ADN de los medicamentos contra el cáncer bloquean la transcripción en las células de los mamíferos. La reparación por escisión de nucleótidos elimina estos adductos de platino-ADN, restaurando la transcripción, crucial para la comprensión de los mecanismos de las drogas.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Investigación del cáncer Investigación del cáncer.
Sus antecedentes:
- Los medicamentos a base de platino son agentes anticancerígenos vitales.
- Su eficacia se basa en el enlace cruzado del ADN y la inhibición de la transcripción.
- Comprender el procesamiento de adyuctos de platino-ADN in vivo es crítico.
Objetivo del estudio:
- Para investigar el procesamiento de enlaces cruzados platino-ADN específicos del sitio en células de mamíferos vivos.
- Para aclarar el papel de la reparación por escisión de nucleótidos en la mitigación del bloqueo de transcripción inducido por platino.
Principales métodos:
- Desarrolló un ensayo de células vivas utilizando plásmidos reporteros de luciferasa con lesiones definidas de ADN de platino.
- Plasmidos platinados introducidos globalmente o específicamente en el sitio en las células de mamíferos.
- Células utilizadas con sistemas de reparación por escisión de nucleótidos (NER) competentes o deficientes.
Principales resultados:
- Los enlaces cruzados platino-ADN impiden la progresión de la ARN polimerasa, inhibiendo la transcripción.
- La reparación por escisión de nucleótidos (NER, por sus siglas en inglés) elimina efectivamente los adductos de ADN de platino.
- Las células competentes en NER mostraron una transcripción restaurada después del daño del ADN de platino, a diferencia de las células deficientes en NER.
Conclusiones:
- Los enlaces cruzados platino-ADN se procesan mediante la reparación por escisión de nucleótidos (NER) en células vivas.
- El NER es esencial para restaurar la transcripción interrumpida por los medicamentos anticancerígenos a base de platino.
- Este estudio proporciona in vivo conocimientos mecanicistas sobre la acción y la resistencia del fármaco platino.
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