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Cell-free chromatin from dying cells implicated in chemotherapy toxicity

24 Jul 2017

The toxic side-effects of chemotherapy appear to be induced by cell-free chromatin (cfCh) fragments released from dying cells, triggering DNA damage, apoptosis and inflammation in healthy cells, thereby exaggerating or amplifying the toxic effects caused by the drugs themselves, according to a study.

Importantly, such an event could be prevented by concurrent treatment with cfCh neutralizing/degrading agents.

Researchers have previously reported that cfCh fragments released from drug-induced cell death can readily enter into healthy cells of the body to cause DNA double-strand breaks, apoptosis and inflammation. [J Biosci 2015;40:91-111; Cell Death Dis 2017;doi:10.1038/cddiscovery.2017.15]

In the present investigation, researchers tested the hypothesis that much of the toxicity of chemotherapy might be due to release of large quantities of cfCh from dying cells by administering cfCh neutralizing/degrading agents (pullulan-histone antibody nanoconjugates [CNPs], DNase I and resveratrol-copper) in mice and examine whether chemotherapy-induced toxicity could be minimized.

CNPs, DNase I and resveratrol-copper were concurrently administered with five different chemotherapeutic agents including adriamycin (10 mg/kg), cyclophoshamide (100 mg/kg), cisplatin (20 mg/kg), methotrexate (25 mg/kg) and paclitaxel (10 mg/kg).

Results showed a significant reduction in chemotherapy-induced surge of cfCh, inflammatory cytokines C-reactive protein, interleukin (IL)-6, interferon gamma and tumour necrosis factor-alpha in blood.

Concurrent treatment with cfCh neutralizing/degrading agents also resulted in significant 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.

Survival analysis showed that the agents significantly prevented prolonged neutropenia after a single dose of adriamycin and reduced death after a lethal dose of adriamycin.

The present data have significant clinical implications, researchers said. “They suggest that cardiac, gastrointestinal, neurological, cutaneous and reproductive side-effects of chemotherapy which include cardiac failure, nausea, vomiting, diarrhoea, neurotoxicity, sterility and hair loss can be potentially prevented by administration of cfCh neutralizing/degrading agents administered concurrently with chemotherapy.”

“Similarly, bone marrow suppression and the resultant neutropenia as well as the occasional fatality resulting from chemotherapy may also appear to be preventable. If our results are successfully translated into the clinic, it might help to bring relief to thousands of patients who are prescribed chemotherapy for cancer worldwide every day,” they pointed out.

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