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

• Published in: British journal of cancer Vol. 103; no. 10; pp. 1588 - 1596
• Main Authors: Daniel, R A, Rozanska, A L, Mulligan, E A, Drew, Y, Thomas, H D, Castelbuono, D J, Hostomsky, Z, Plummer, E R, Tweddle, D A, Boddy, A V, Clifford, S C, Curtin, N J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.11.2010; Nature Publishing Group
• Subjects: 631/154/436/1729; 631/378/1689/1690; 692/308/2778; 692/700/565/1436/1437; Animals; Antineoplastic Agents, Alkylating - therapeutic use; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Brain cancer; Brain research; Cancer Research; Cancer therapies; Cell Division - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Central Nervous System Neoplasms - drug therapy; Central Nervous System Neoplasms - enzymology; Central Nervous System Neoplasms - pathology; Child; Dacarbazine - analogs & derivatives; Dacarbazine - therapeutic use; DNA damage; DNA methylation; DNA Mismatch Repair - drug effects; DNA Repair - drug effects; Drug Resistance; Epidemiology; Humans; Indoles - therapeutic use; Medical research; Medical sciences; Medulloblastoma - drug therapy; Medulloblastoma - enzymology; Medulloblastoma - pathology; Mice; Mice, Nude; Molecular Medicine; Nervous system; Neurology; Oncology; Pediatrics; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Protein Serine-Threonine Kinases - antagonists & inhibitors; Temozolomide; Toxicity; Translational Therapeutics; Transplantation, Heterologous; Tumors; Tumors of the nervous system. Phacomatoses; temozolomide; CNS; PARP; xenograft; medulloblastoma; Antineoplastic agent; Glycosyltransferases; Central nervous system; Transplantation; Heterotransplantation; Cancerology; Surgery; ADP-ribosyltransferase; Graft; Child; Human; Nervous system diseases; Enzyme; Transferases; Malignant tumor; Biological activity; Cerebral disorder; NAD; Alkylating agent; Penetration; Treatment; Animal; Medulloblastoma; Central nervous system disease; Inhibitor; Models; Temozolomide; Pentosyltransferases; Cancer
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/sj.bjc.6605946

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  μ M ), representative of most primary medulloblastomas, were sensitised fourfold by AG-014699; MGMT − MMR + D425Med cells were hypersensitive (GI 50 =9  μ M ) and not sensitised by AG-014699, whereas MGMT + MMR − temozolomide-resistant D283Med cells (GI 50 =807  μ 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.