Histone γH2AX and Poly(ADP-Ribose) as Clinical Pharmacodynamic Biomarkers

Abstract

Tumor cells are often deficient in DNA damage response (DDR) pathways, and anticancer therapies are commonly based on genotoxic treatments using radiation and/or drugs that damage DNA directly or interfere with DNA metabolism, leading to the formation of DNA double-strand breaks (DSB), and ultimately to cell death. Because DSBs induce the phosphorylation of histone H2AX (γH2AX) in the chromatin flanking the break site, an antibody directed against γH2AX can be employed to measure DNA damage levels before and after patient treatment. Poly(ADP-ribose) polymerases (PARP1 and PARP2) are also activated by DNA damage, and PARP inhibitors show promising activity in cancers with defective homologous recombination (HR) pathways for DSB repair. Ongoing clinical trials are testing combinations of PARP inhibitors with DNA damaging agents. Poly(ADP-ribosylation), abbreviated as PAR, can be measured in clinical samples and used to determine the efficiency of PARP inhibitors. This review summarizes the roles of γH2AX and PAR in the DDR, and their use as biomarkers to monitor drug response and guide clinical trials, especially phase 0 clinical trials. We also discuss the choices of relevant samples for γH2AX and PAR analyses. Clin Cancer Res; 16(18); 4532-42. ©2010 AACR.

Dimethylnitrosamine-Induced Reduction in the Level of Poly-ADP-Ribosylation of Histone Proteins of Blood Lymphocytes - a Sensitive and Reliable Biomarker for Early Detection of Cancer

“…Nonetheless, it can be concluded that DMN induced changes in histone proteins by way of reducing their extents of poly ADPribosylation during the initiation stage of DMN induced carcinogenesis. The PAR of histone proteins observed in our study confirms the earlier report of histones being the major target of cellular PAR (Kma and Sharan, 2006;Fontan-Lozano et al, 2010;Redon et al, 2010), making histones the most preferred target proteins for PAR.…”

Heat Shock Protein 90α (Hsp90α) Is Phosphorylated in Response to DNA Damage and Accumulates in Repair Foci

“…Detection of Irradiation-induced Phosphorylation in Irradiated Bulb Hair-Phosphorylated H2AX has been identified as a potentially useful biomarker of exposure to DNA-damaging agents (52). We thought that Hsp90␣, which is highly abundant in all cell types, would be a useful alternative marker.…”

“…Correlation between Basal P-Hsp90␣ Levels and ␥-H2AX Content in Human Tumors and Possible Use of P-Hsp90␣ as a Biomarker of DNA Damage-Phosphorylated H2AX has been identified as a useful biomarker in clinical oncology (52,53). First, ␥-H2AX quantification can be used to assess the efficacy of DNA damage-inducing chemo-or radiotherapy (25).…”

The Arf/p53 Protein Module, Which Induces Apoptosis, Down-regulates Histone H2AX to Allow Normal Cells to Survive in the Presence of Anti-cancer Drugs

“…Although some drugs were specifically developed for targeted cancer chemotherapy (1,2), most anti-cancer drugs used today are DNA-damaging agents that induce cancer cell death by interfering with checkpoint responses (3)(4)(5)(6)(7)(8)(9). Because these anti-cancer drugs are administered without a specialized delivery system, they often cause side effects.…”