Central nervous system penetration and enhancement of temozolomide activity in childhood medulloblastoma models by poly(ADP-ribose) polymerase inhibitor AG-014699

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 mu M), representative of most primary medulloblastomas, were sensitised fourfold by AG-014699; MGMT(-) MMR+ D425Med cells were hypersensitive (GI(50)=9 mu M) and not sensitised by AG-014699, whereas MGMT(+) MMR- temozolomide-resistant D283Med cells (GI(50)=807 mu 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. British Journal of Cancer (2010) 103, 1588-1596. doi:10.1038/sj.bjc.6605946 www.bjcancer.com Published online 26 October 2010 (C) 2010 Cancer Research UK