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 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.


CONCLUSIONS
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.
Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne, NE2 4HH, UK.
R A
RA
Daniel
A L
AL
Rozanska
E A
EA
Mulligan
Y
Y
Drew
H D
HD
Thomas
D J
DJ
Castelbuono
Z
Z
Hostomsky
E R
ER
Plummer
D A
DA
Tweddle
A V
AV
Boddy
S C
SC
Clifford
N J
NJ
Curtin
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016543:Central Nervous System Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D002648:Child; D053843:DNA Mismatch Repair / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008527:Medulloblastoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077204:Temozolomide; D014183:Transplantation, Heterologous
D018906:Antineoplastic Agents, Alkylating; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D003606:Dacarbazine; C531549:rucaparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D017346:Protein Serine-Threonine Kinases; D000077204:Temozolomide