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 GI(50)=220 μM), representative of most primary medulloblastomas, were sensitised fourfold by AG-014699; MGMT⁻ MMR(+) D425Med cells were hypersensitive (GI(50)=9 μM) and not sensitised by AG-014699, whereas MGMT(+) MMR⁻ 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.

• Authors: R A Daniel, A L Rozanska, E A Mulligan, Y Drew, H D Thomas, D J Castelbuono, Z Hostomsky, E R Plummer, D A Tweddle, A V Boddy, S C Clifford, N J Curtin
• Journal: British journal of cancer (Br J Cancer) Vol. 103 Issue 10 Pg. 1588-96 (Nov 09 2010) ISSN: 1532-1827 [Electronic] England
• PMID: 20978505 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Alkylating
• Indoles
• Poly(ADP-ribose) Polymerase Inhibitors
• Dacarbazine
• rucaparib
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Protein Serine-Threonine Kinases
• Temozolomide

Topics

• Animals
• Antineoplastic Agents, Alkylating (therapeutic use)
• Cell Division (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Central Nervous System Neoplasms (drug therapy, enzymology, pathology)
• Child
• DNA Mismatch Repair (drug effects)
• DNA Repair (drug effects)
• Dacarbazine (analogs & derivatives, therapeutic use)
• Humans
• Indoles (therapeutic use)
• Medulloblastoma (drug therapy, enzymology, pathology)
• Mice
• Mice, Nude
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerase Inhibitors
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Temozolomide
• Transplantation, Heterologous