title: Evaluation of poly (ADP-ribose) polymerase inhibitor ABT-888 combined with radiotherapy and temozolomide in glioblastoma.
abstract: BACKGROUND
  The cytotoxicity of radiotherapy and chemotherapy can be enhanced by modulating DNA repair. PARP is a family of enzymes required for an efficient base-excision repair of DNA single-strand breaks and inhibition of PARP can prevent the repair of these lesions. The current study investigates the trimodal combination of ABT-888, a potent inhibitor of PARP1-2, ionizing radiation and temozolomide(TMZ)-based chemotherapy in glioblastoma (GBM) cells.
  
  
  METHODS
  Four human GBM cell lines were treated for 5 h with 5 μM ABT-888 before being exposed to X-rays concurrently with TMZ at doses of 5 or 10 μM for 2 h. ABT-888's PARP inhibition was measured using immunodetection of poly(ADP-ribose) (pADPr). Cell survival and the different cell death pathways were examined via clonogenic assay and morphological characterization of the cell and cell nucleus.
  
  
  RESULTS
  Combining ABT-888 with radiation yielded enhanced cell killing in all four cell lines, as demonstrated by a sensitizer enhancement ratio at 50% survival (SER50) ranging between 1.12 and 1.37. Radio- and chemo-sensitization was further enhanced when ABT-888 was combined with both X-rays and TMZ in the O6-methylguanine-DNA-methyltransferase (MGMT)-methylated cell lines with a SER50 up to 1.44. This effect was also measured in one of the MGMT-unmethylated cell lines with a SER50 value of 1.30. Apoptosis induction by ABT-888, TMZ and X-rays was also considered and the effect of ABT-888 on the number of apoptotic cells was noticeable at later time points. In addition, this work showed that ABT-888 mediated sensitization is replication dependent, thus demonstrating that this effect might be more pronounced in tumour cells in which endogenous replication lesions are present in a larger proportion than in normal cells.
  
  
  CONCLUSIONS
  This study suggests that ABT-888 has the clinical potential to enhance the current standard treatment for GBM, in combination with conventional chemo-radiotherapy. Interestingly, our results suggest that the use of PARP inhibitors might be clinically significant in those patients whose tumour is MGMT-unmethylated and currently derive less benefit from TMZ.
authors.affiliation: University of Surrey, Guildford, Surrey, GU2 7XH, UK. lara.barazzuol@gmail.com
authors.forename: Lara
authors.initials: L
authors.lastname: Barazzuol
authors.forename: Raj
authors.initials: R
authors.lastname: Jena
authors.forename: Neil G
authors.initials: NG
authors.lastname: Burnet
authors.forename: Lisiane B
authors.initials: LB
authors.lastname: Meira
authors.forename: Jonathan C G
authors.initials: JC
authors.lastname: Jeynes
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Kirkby
authors.forename: Norman F
authors.initials: NF
authors.lastname: Kirkby
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001562:Benzimidazoles / Q000008:administration & dosage*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy / Q000379:methods*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma; D006801:Humans; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; C521013:veliparib; D003606:Dacarbazine; D011065:Poly(ADP-ribose) Polymerases; D000077204:Temozolomide