Molecular Aspects of Chemical Radiosensitization

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Abstract
The low sensitivity of most solid tumors to ionizing radiations is due in part to the low oxygen content within the malignant cells. Attempts to overcome this radio-resistance through the use of hyperbaric oxygen and of neutron beams in radiotherapy have been at least in part disappointing. A more promising approach has been the search for chemical compounds which would act as efficient sensitizers of hypoxic cells. A variety of chemicals was found to sensitize bacterial and mammalian cells to radiations in vivo. 2,3,6,12,13,17,18,21,22,49) However such radiosensitizers have been shown to be less efficient in vivo experiments. 14-16,28,29,40,46,56) These compounds must have favourable pharmacological and toxicological properties such as good specificity for the poorly oxygenated cells, fast diffusion and penetration at a sufficient concentration into the tumor cells, absence of toxicity at therapeutic doses for normal tissues and high resistance to metabolic degradation. The cellular mode of action of these radiosensitizing drugs remains obscure. However the radiosentization may be accounted for either by radiation biochemical or (and) by chemical mechanisms. Dia-mide and N-ethyl maleimide or NEM (Fig. 1) which respectively may oxidize32) and bind to sulfhydryl compounds335 act mainly through the former mechanism.24) A reasonable explanation for their radiosensititizing action lies on the lowering of the cellular concentration of the endogeneous sulfhydryl agents which play a role in radioprotection. However rapid mixing experiments have shown that the radiosensi-tization of anaerobic bacteria by NEM occurs only a few milliseconds after the addition of the chemical.4) Furthermore it was recently postulated that the mechanism of action of diamide looks like that of so-called electron-affinic sensitizers.54)

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