Investigation of the effects of hydrogen peroxide in combination with ionising radiation in cancer
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Introduction In the early 2000s, Japanese colleagues reported sensitisation of normal and tumour cell lines to cytotoxic doses of ionising radiation (IR) by low concentrations of hydrogen peroxide (H2O2), research that prompted clinical studies testing intratumoural (IT) injections of 0.5% H2O2 in 1% sodium hyaluronate gel during radiotherapy in patients with inoperable breast cancer. Five-year local control rates were substantially higher than expected from the radiotherapy dose intensities used, with no additional late adverse effects. Methods Using the radioresistant cell lines HCT116 and HN5, the effect of H2O2 + IR was investigated in 2D clonogenic survival and 3D spheroid growth assays. A dual hypoxia marker technique was used to capture the effect of IT H2O2 in murine xenografts. In paralleL, a phase I clinical trial of IT H2O2 + radiotherapy was conducted in 12 patients with breast cancer to evaluate safety and cute toxicity. Results 2D clonogenic assays did not confirm sensitisation of HCT116 or HN5 under normoxic conditions. Growth inhibition was demonstrated in HCT116 spheroids treated with H2O2 + IR, compared with H2O2/IR alone. Xenograft tumours injected with H2O2 + sodium hyaluronate exhibited a reduction in hypoxia staining compared to baseline. A significant difference in pimonidazole versus CCI-103F staining was demonstrated in H2O2-injected tumours (p0=02), with no significant difference in the control groups. The phase I clinical trial confirmed safety with no additional toxicity compared to RT alone. Conclusion 3D spheroid results are in keeping with clinical reports of enhancement of radiation effect by H2O2. Reoxygenation by IT H2O2 may be an important mechanism by which tumour response is enhanced for therapeutic gain, and which has implications for scheduling of H2O2 relative to radiotherapy in the clinical setting. If this method of increasing oxygen delivery to tumours is confirmed to be successful, it has potential to be utilised in several other tumour types.
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Institute of Cancer Research (University Of London)