Poly (ADP-Ribose) polymerase inhibitor MK-4827 together with radiation as a novel therapy for metastatic neuroblastoma.

Abstract

BACKGROUND/AIM:

To assess poly (ADP-ribose) polymerase (PARP) inhibitor MK-4827 together with radiation for the treatment of neuroblastoma.

MATERIALS AND METHODS:

Clonogenic survival assays were used to assess MK-4827, radiation and combination thereof in four neuroblastoma cell lines. In vivo efficacy was tested in a murine xenograft model of metastatic neuroblastoma. In vivo targeted inhibition and biological effects included measurement of cleaved caspase-3, γ-H2AX, and Ki 67 by immunohistochemistry (IHC) and poly-ADP-ribose by Enzyme-Linked Immunosorbent Assay.

RESULTS:

Treatment of neuroblastoma cell lines reduced clonogenicity and resulted in additive effects with radiation. In vivo treatment with MK-4827 and radiation prolonged survival (p<0.01) compared to single modalities. In vivo superiority of MK-4827 plus radiation was further documented by significant elevations of cleaved caspase-3 and γ-H2AX in tumors from the combination group compared to single modality cohorts.

CONCLUSION:

Combination of MK-4827 and radiation might provide effective therapy for children with high-risk neuroblastoma.

• Authors: Sabine Mueller, Samhita Bhargava, Annette M Molinaro, Xiaodong Yang, Ilan Kolkowitz, Aleksandra Olow, Noor Wehmeijer, Sharon Orbach, Justin Chen, Katherine K Matthay, Daphne A Haas-Kogan
• Journal: Anticancer research (Anticancer Res) Vol. 33 Issue 3 Pg. 755-62 (Mar 2013) ISSN: 1791-7530 [Electronic] Greece
• PMID: 23482742 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Enzyme Inhibitors
• H2AX protein, human
• Histones
• Indazoles
• Piperidines
• Poly(ADP-ribose) Polymerase Inhibitors
• Radiation-Sensitizing Agents
• Caspase 3
• niraparib

Topics

• Animals
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Chemoradiotherapy
• Enzyme Inhibitors (therapeutic use)
• Female
• Histones (analysis)
• Humans
• Indazoles (therapeutic use)
• Mice
• Neoplasm Metastasis
• Neuroblastoma (enzymology, pathology, therapy)
• Piperidines (therapeutic use)
• Poly(ADP-ribose) Polymerase Inhibitors
• Radiation-Sensitizing Agents (therapeutic use)