Ypg

Biomolecule Biomolecule radical

Repaired biomolecule

FIGURE 4.41 Repair of biomolecule radicals by glutathione.

Oxidized biomolecule

FIGURE 4.42 Enhancement of the effects of ionizing radiation by oxygen.

repaired because the action of glutathione on them does not lead back to the biomolecule, but to an oxidized derivative (Fig. 4.42).

For this reason, tumor hypoxia is associated with resistance to radiotherapy and also to some types of chemotherapy. In these hypoxic tumors, some types of chemical agents can play a similar role to oxygen, and therefore they can be used to increase the sensitivity toward radiotherapy. These compounds are known as radiosensitizers96 and are being applied to a growing number of human cancers like those of cervix, head and neck, or lung cancer.97 Another interesting application of some radiosensitizers is their use as hypoxia markers to accurately measure oxygen gradients at the cellular level.98

The first compounds that were studied in clinical trials as hypoxic radiosensi-tizers were nitroimidazoles. The mechanism of hypoxic-cell sensitizing by the nitro derivatives is based on their ability to react with biomolecule radicals giving a radical adduct that cannot be repaired, thereby acting as oxygen surrogates (Fig. 4.43A). Alternatively, addition of the biomolecule radical to the nitro group gives nitro radical anions (Fig. 4.43B).

Nitro radical anions are cytotoxic in themselves in hypoxic environments, although normally only at doses too high to be achieved in clinical situations. However, this cytotoxicity is reinforced by the generation of other radical species, some of which are shown in Fig. 4.44. It is interesting to mention in this context that the antibacterial and antiprotozoal activity of many nitrohetero-cycles is explained by one-electron reduction of the nitro group to nitro radical anions.

The first nitro compounds to be clinically studied as radiosensitizers, in the early 1970s, were metronidazole and specially misonidazole, which were studied in a large number of clinical assays. Despite initial promise, these clinical studies

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