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types of hypoxia-based strategies for tumor-specific prodrug activation will be mentioned in Sections 11.3 (GDEPT therapy) and 11.4 (ADEPT therapy).

One of the enzymes involved in the one-electron reduction reactions needed for hypoxia-selective bioactivation is cytochrome P450 reductase, a flavoprotein that functions as an electron donor for P450. This enzyme is able to reduce aldehydes, quinones, and N-oxides, among other functional groups, directly or via P450s. Some drugs can be reduced by other enzymes, like P450 itself or nitroreductases.

The best-known aromatic N-oxide used as an antitumor drug is tirapazamine (TPZ), which undergoes an enzymatic one-electron reduction to the TPZ radical. In normal cells, this species reacts with oxygen to give back TPZ, together with a superoxide radical. However, in hypoxic environments the TPZ radical undergoes two different types of fragmentation reactions (see Section 9 of Chapter 4), leading to hydroxyl and benzotriazinyl (BTZ) radicals, which cause DNA strand cleavage and topoisomerase II poisoning (Fig. 11.5). One advantage of TPZ is its potentiation of the efficacy under hypoxic conditions of radiotherapy and some chemotherapeutic drugs, including cisplatin.

Aliphatic N-oxides can be considered as good prodrugs of intercalating agents bearing side chains with basic tertiary amino groups. The rationale for the use of these compounds as prodrugs is that they have a greatly decreased affinity for DNA because the negatively charged N-oxide oxygen atoms prevent their interaction with the anionic phosphate groups in DNA.5 The best-known aliphatic N-oxide hypoxia-activated prodrug is the anthraquinone AQ4N, which is under clinical trials.6 Its reduction followed by protonation furnishes the active species

Normal cells

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