Platinum based radiochemotherapies: Free radical mechanisms and radiotherapy sensitizers

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Abstract

The radiosensitizing ability of Pt drugs can in the first instance be predicted based on the ease that they undergo activation by electron attachment accompanied by structural modification prior to forming Pt-DNA adducts. Unlike cisplatin, carboplatin and nedaplatin, oxaliplatin does not undergo a facile dissociative electron transfer reaction when an electron is attached. However, oxaliplatin undergoes a facile nucleophilic assisted proton coupled electron transfer (NAPCET), which may be key element of the success of FOLFOX radiochemotherapy against certain cancers. Under acidic conditions, oxaliplatin is a superior radiosensitizer to cisplatin or carboplatin, in the presence of nucleophiles such as water, chloride ions or thiols. Oxaliplatin may also be activated as a platinating agent and radiosensitizer by a minor hydrogen radical free radical mechanism as well as the more dominant NAPCET mechanism. The radiosensitizing synergism that is shown when oxaliplatin is combined with 5-fluorouracil can be due to the formation of a π complex between the two drugs, which is more potent under acidic conditions. These factors have a bearing on Pt based chemotherapy clinical regimes as well as clinical radiochemotherapy regimes, and could be a basis for optimizing how such drug schedules are administered.

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