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Aliviar la toxicidad de los fármacos contra el cáncer inhibiendo una enzima bacteriana
Bret D Wallace1, Hongwei Wang, Kimberly T Lane
1Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.
Science (New York, N.Y.)
|November 6, 2010
Resumen
Los investigadores desarrollaron inhibidores dirigidos para las enzimas bacterianas que causan diarrea severa por el medicamento contra el cáncer de colon CPT-11. Estos inhibidores protegen a los microbios intestinales y reducen la toxicidad de los medicamentos en ratones, ofreciendo una nueva estrategia para el tratamiento del cáncer.
Área de la Ciencia:
- Microbiología Microbiología.
- Farmacología Farmacología.
- La bioquímica es la bioquímica.
Sus antecedentes:
- La diarrea severa es un efecto secundario que limita la dosis de CPT-11, un medicamento de quimioterapia común para el cáncer de colon.
- Esta toxicidad es causada por las β-glucuronidasas bacterianas que reactivan CPT-11 en el intestino.
- Dirigirse selectivamente a estas enzimas bacterianas podría mitigar la toxicidad sin dañar las bacterias intestinales beneficiosas.
Objetivo del estudio:
- Para identificar inhibidores potentes y selectivos de las β-glucuronidasas bacterianas.
- Evaluar la eficacia de estos inhibidores contra las enzimas bacterianas in vitro e in vivo.
- Evaluar el potencial terapéutico de estos inhibidores para prevenir la toxicidad inducida por la CPT-11.
Principales métodos:
- Cribado de alto rendimiento para identificar inhibidores bacterianos de la β-glucuronidasa.
- Pruebas enzimáticas para determinar la potencia inhibidora y la selectividad contra bacterias y mamíferos ortólogos.
- Análisis de la estructura cristalina para comprender las bases de la selectividad.
- Prueba de inhibidores en bacterias aeróbicas y anaeróbicas vivas y células de mamíferos.
- Estudios in vivo en ratones para evaluar la protección contra la toxicidad del CPT-11.
Principales resultados:
- Se identificaron potentes inhibidores bacterianos de la β-glucuronidasa.
- Los inhibidores demostraron una alta selectividad para las enzimas bacterianas sobre el ortólogo de mamíferos, basado en características estructurales únicas.
- Los inhibidores fueron efectivos contra la enzima diana en las bacterias sin causar la muerte bacteriana o dañar las células de mamíferos.
- La administración oral de un inhibidor protegió con éxito a los ratones de la diarrea inducida por CPT-11.
Conclusiones:
- La inhibición selectiva de las enzimas microbianas es una estrategia viable para mejorar la eficacia quimioterapéutica.
- Este enfoque puede mitigar la toxicidad inducida por fármacos al dirigirse a actividades microbianas específicas.
- El desarrollo de tales inhibidores dirigidos ofrece una vía prometedora para mejorar los resultados de los pacientes con cáncer.
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