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San Diego, CA, United States

Daniel R.A.,Northumbria University | Rozanska A.L.,Northumbria University | Mulligan E.A.,Northumbria University | Drew Y.,Northumbria University | And 8 more authors.
British Journal of Cancer | Year: 2010

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 GI50 220 μ), representative of most primary medulloblastomas, were sensitised fourfold by AG-014699; MGMT MMR D425Med cells were hypersensitive (GI509 μ) and not sensitised by AG-014699, whereas MGMT+ MMR-temozolomide-resistant D283Med cells (GI50 807 M) 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. © 2010 Cancer Research UK All rights reserved.

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