[Radiation sensitizers: with special reference to hypoxic cell sensitizers]

Recent advances in radiation chemistry and radiation biology have led to the combined use of radiosensitizing agents with radiation in the treatment of radioresistant tumors. Various chemicals, including cancerocidal drugs, are used, although radiation sensitizers are defined as drugs which can increase cellular radiosensitivity but have no direct cancerocidal effect. At least four classes of agents, pyrimidine analogues, hypoxic cell sensitizers, PLDR inhibitors and thiol-depleting agents, can modify radiosensitivity and have potential for differential sensitization. Pyrimidine analogues are incorporated into DNA in replicating tumor cells, and can sensitize these cells to radiation up to a factor of 3. Results of clinical trials of intra-arterial infusion of BUdR have not proved satisfactory, especially with regard to long-term survival, possibly because of the existence of non-replicating cells in the tumor. The latter two are still in the experimental stage of study. The radioresistance of hypoxic cells in tumor has been regarded as one of the limiting factors in the local control of cancer by radiation. Attempts to improve the situation involve high-LET radiation and combined use of chemicals, such as oxygen, prefluorochemicals and electron-affinic compounds, with low-LET radiation. Although some clinical trials in head and neck cancer and in cervical cancer have yielded positive results in patients treated using hyperbaric oxygen, attempts have been made to devise other methods, such as those using perfluorochemicals with normobaric oxygen, because of the technical difficulty involved with the former method. A more promising and easier method is the combined use of electron-affinic chemicals, which like oxygen can sensitize the hypoxic cells. Misonidazole (alpha 2-nitroimidazole derivative) was found to be an excellent sensitizer of this kind in cultured mammalian cells and in some rodent tumors. Several randomized clinical trials to determine its efficacy have been carried out on a word-wide scale, but most of them failed to demonstrate any beneficial effect, mainly because of the drug's neurotoxicity which limits its dose. After misonidazole, many researchers have made every effort to develop more efficient hypoxic cell sensitizers. The present state and future prospects of study were reviewed with special reference to studies currently being undertaken in Japan.