tumors.89,90 It has also been shown that electric pulses combined with TPZ and radiotherapy (electroradiochemotherapy) are more efficient than TPZ and radiation (radiochemotherapy).91

One-electron reduction of TPZ by NADPH-dependent cytochrome P450 reductase (P450R) leads to the formation of the TPZ radical, which is rapidly destroyed by oxygen in normal cells, leading to superoxide radical, which is thought to be responsible for the muscle cramps seen in patients given the drug. Under hypoxic conditions, the TPZ radical can undergo homolytic cleavage to the reduced species SR 4317 and a hydroxyl radical. Both radicals can react with DNA, but damage caused by TPZ can be detected both at the DNA backbone and the heterocyclic bases and can therefore be considered as typical of hydroxyl radicals.92 Another DNA-damaging species generated in the metabolism of TPZ is the benzotriazinyl (BTZ) radical,93 formed by loss of water (Fig. 4.36). Doublestrand breaks are caused, at least partially, by poisoning of topoisomerase II, either by direct damage from the radical species derived from TPZ or from radicals generated on the DNA molecules, which are the topoisomerase II substrates.94

Another reactive species that is generated by loss of a molecule of water from the TPZ radical is the BTZ radical, which is also responsible for DNA and topoisomerase damage (Fig. 4.37).

Besides its ability to generate DNA-damaging radicals, TPZ itself can also react with DNA radicals arising from these reactions, playing a role similar to the oxygen molecule. This dual role helps to explain the very high efficiency of TPZ

Normal cells

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