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

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 GI50=220 μ), representative of most primary medulloblastomas, were sensitised fourfold by AG-014699; MGMT− MMR+ D425Med cells were hypersensitive (GI50=9 μ) and not sensitised by AG-014699, whereas MGMT+ MMR− temozolomide-resistant D283Med cells (GI50=807 μ) 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.

Discovery of 1-substituted benzyl-quinazoline-2,4(1H,3H)-dione derivatives as novel poly(ADP-ribose)polymerase-1 inhibitors

“…The suspension was cooled below 5°C and precipitates were collected by filtriation. After washing with methanol (5 mL) and water (5 mL 1.14-1.38 (m, 9H); 13 170.99, 161.80, 153.33, 150.58, 140.82, 139.51, 136.97, 135.22, 129.09, 127.57, 122.70, 121.40, 117.97, 116.43, 115.82, 115.11 …”

The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies

“…Secondly, it is well known that germline defects may modulate the response to treatment since DNA-repair mechanisms make cells prone to the effects of DNA-damaging chemotherapy [13–15]. It is important to notice that majority of evidence about the impact of DNA-repair genes defects on toxicity in medulloblastoma comes from either description of single cases [16, 17] or from mouse models and cell lines experiments [13, 18] but not from systemic clinical based investigation. Therefore, all these data indicate that DNA repair genes are a promising targets possibly linked both to development of tumor and response to therapy in medulloblastoma .…”

Efficacy of Asparaginase Erwinia chrysanthemi With and Without Temozolomide Against Glioma Cells and Intracranial Mouse Medulloblastoma

“…Temozolomide prolongs patient survival and delays disease progression (5). It showed anti-medulloblastoma activity in mice (6) and in patients with recurrent medulloblastomas or primitive neuroectodermal tumors (7). Temozolomide has dose-limiting hematological toxicities, like other DNA-alkylating agents (5,8).…”