Central nervous system penetration and enhancement of temozolomide activity in childhood medulloblastoma models by poly(ADP-ribose) polymerase inhibitor AG-014699.
Br J Cancer
; 103(10): 1588-96, 2010 Nov 09.
Article
en En
| MEDLINE
| ID: mdl-20978505
ABSTRACT
BACKGROUND:
Temozolomide shows activity against medulloblastoma, the most common malignant paediatric brain tumour. Poly(ADP-ribose) polymerase (PARP) inhibitors enhance temozolomide activity in extracranial adult and paediatric human malignancies.METHODS:
We assessed the effect of AG-014699, a clinically active PARP inhibitor, on temozolomide-induced growth inhibition in human medulloblastoma models. Pharmacokinetic, pharmacodynamic and toxicity assays were performed in tumour-bearing mice.RESULTS:
Sensitivity to temozolomide in vitro was consistent with methylguanine methyltransferase (MGMT) and DNA mismatch repair (MMR) status; MGMT(+) MMR(+) D384Med cells (temozolomide GI(50)=220 µM), representative of most primary medulloblastomas, were sensitised fourfold by AG-014699; MGMTâ» MMR(+) D425Med cells were hypersensitive (GI(50)=9 µM) and not sensitised by AG-014699, whereas MGMT(+) MMRâ» temozolomide-resistant D283Med cells (GI50=807 µM) were sensitised 20-fold. In xenograft models, co-administration of AG-014699 produced an increase in temozolomide-induced tumour growth delay in D384Med xenografts. Consistent with the in vitro data, temozolomide caused complete tumour regressions of D425Med xenografts, whereas D283Med xenografts were relatively resistant. AG-014699 was not toxic, accumulated and reduced PARP activity ≥75% in xenograft and brain tissues.CONCLUSION:
We show for the first time central nervous system penetration and inhibition of brain PARP activity by AG-014699. Taken together with our in vitro chemosensitisation and toxicity data, these findings support further evaluation of the clinical potential of AG-014699-temozolomide combinations in intra-cranial malignancies.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Neoplasias del Sistema Nervioso Central
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Antineoplásicos Alquilantes
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Dacarbazina
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Inhibidores de Poli(ADP-Ribosa) Polimerasas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Child
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Humans
Idioma:
En
Revista:
Br J Cancer
Año:
2010
Tipo del documento:
Article
País de afiliación:
Reino Unido