Evaluation of poly (ADP-ribose) polymerase inhibitor ABT-888 combined with radiotherapy and temozolomide in glioblastoma

Radiation Oncology

Norman F Kirkby³  Karen J Kirkby⁴  Jonathan C G Jeynes⁴  Lisiane B Meira¹  Neil G Burnet²  Raj Jena²  Lara Barazzuol⁴ 

[1] Department of Biochemistry and Physiology, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU 7XH, UK;Department of Oncology, University of Cambridge, Oncology Centre, Addenbrooke’s Hospital, PO Box 193, Cambridge, CB2 0QQ, UK;Chemical and Process Engineering, Faculty of Engineering & Physical Sciences, University of Surrey, Guildford, Surrey, GU 7XH, UK;Ion Beam Centre, Faculty of Engineering & Physical Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK

关键词: Temozolomide;    Radiation;    ABT-888;    PARP inhibition;    Glioblastoma;   

Others  :  1154369
DOI  :  10.1186/1748-717X-8-65

 received in 2012-11-09, accepted in 2013-03-12,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Barazzuol et al.; licensee BioMed Central Ltd.

【 图 表 】

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