Ii

Nitroxide radical

Nitroso compound Nitrous acid

FIGURE 4.44 Cytotoxic radical species generated from nitro radical anions.

were disappointing and the combination of misonidazole with radiotherapy failed to show significant benefits, with some studies reported a significant neu-rotoxicity. In 1980s, other 2-nitroimidazoles (etanidazole and pimonidazole) were studied as radiosensitizers. Because of their lower lipophilicity as compared with misonidazole, both compounds showed lower penetration in the nervous system and a more rapid excretion, which result in lower neurotoxicity, but their clinical data did not demonstrate any benefit for radiotherapy. Subsequently, some of the newer 5-nitroimidazoles, like nimorazole and ornidazole, entered the clinical trials, with similarly discouraging results.

In the case of RSU-1069, a high efficiency has been observed with certain tumors such as the KHT sarcoma, but this effect seems to be due to cytotoxicity of the compound toward hypoxic cells rather than radiosensitization. Other bioreductive antitumor agents (hypoxic cytotoxins), particularly the previously mentioned porfiromycin and TPZ, have shown a great efficacy in combination with radiotherapy.99 For a more detailed discussion of the cytotoxicity of these hypoxia-selective nitro compounds, see Section 2.2.3 of Chapter 11.

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