Hypoxic cell radiosensitizers in the treatment of malignant brain tumors

Radiation therapy provides the most effective adjuvant treatment for patients with malignant brain tumors, but brain intolerance to potentially curative doses of radiation is limiting. Solid tumors are thought to contain a substantial population of cells that are hypoxic; because much of the cell kill caused by ionizing radiation is the result of an oxygen-dependent, free radical-mediated attack on deoxyribonucleic acid, hypoxic tumor cells are known to be radioresistant and are therefore a barrier to cure. With the hope of improving the therapeutic ratio of brain tumor radiation therapy, hypoxic cell radiosensitizers are being evaluated. Two nitroimidazoles, metronidazole and misonidazole, have received the most attention. These compounds are thought to mimic oxygen by "fixing" the free free radical-induced damage caused by radiation in tumor cells. Clinical trials ae providing considerable information about the pharmacokinetics and toxicities of these agents. The preliminary results obtained in clinical trials with brain tumor patients are somewhat discouraging; drug toxicity limits the number of radiation treatments with which a sensitizer may be given. The results of ongoing clinical trials with metronidazole and misonidazole and the identificiation of new, less toxic hypoxic cells sensitizers may improve the potential for this modality of therapy.