Prevention of chemotherapy toxicity by agents that neutralize or degrade cell-free chromatin.

ABSTRACT

BACKGROUND: Toxicity associated with chemotherapy is a major therapeutic challenge and is caused by chemotherapy-induced DNA damage and inflammation. We have recently reported that cell-free chromatin (cfCh) fragments released from dying cells can readily enter into healthy cells of the body to integrate into their genomes and induce DNA double-strand breaks, apoptosis and inflammation in them. We hypothesized that much of the toxicity of chemotherapy might be due to release of large quantities of cfCh from dying cells that could trigger an exaggerated DNA damage, apoptotic and inflammatory response in healthy cells over and above that caused by the drugs themselves. METHODS: We tested this hypothesis by administering cfCh neutralizing/degrading agents namely, anti-histone antibody complexed nanoparticles, DNase I and a novel DNA degrading agent-Resveratrol-Cu concurrently with five different chemotherapeutic agents to examine if chemotherapy-induced toxicity could be minimized. RESULTS: We observed (i) significant reduction in chemotherapy-induced surge of cfCh in blood; (ii) significant reduction in chemotherapy-induced surge of inflammatory cytokines CRP, IL-6, IFNγ and TNFα in blood; (iii) abolition of chemotherapy-induced tissue DNA damage (γH2AX), apoptosis (active caspase-3) and inflammation (NFκB and IL-6) in multiple organs and peripheral blood mononuclear cells; (iv) prevention of prolonged neutropenia following a single injection of adriamycin and (v) significant reduction in death following a lethal dose of adriamycin. CONCLUSION: Our results suggest that toxicity of chemotherapy is caused to a large extent by cfCh released from dying cells and can be prevented by concurrent treatment with cfCh neutralizing/degrading agents.