Radioprotection in Vivo: Cellular Heterogeneity and Fractionation

The curative treatment of cancer by radiotherapy is limited by the sensitivity of critical normal tissues surrounding the tumour that are inevitably included in the irradiation volume. In the last decade two new developments have progressed from the experimental stage in animals to clinical testing: Radiosensitizers that appear specific for tumour cells and radioprotectors that appear specific for normal tissues have both been developed. Of these the prototype compounds are nitroimidazole, misonidazole (miso), as a radiosensitizer (l) and the phosphorylated aminothiol WR-2721 (S-2-(3-amino-propylamino) ethyl phosphorothioic acid) as a radioprotector (2). The specificity of action of these agents does not relate to phenotypic alterations connected with the malignant transformation of cells, but rather to differences in regional oxygen tensions that result from the poor vascularity of tumours. The inadequate vascular array leads to regions of hypoxia which confer radloresistance (by a factor of 2.5 to 3.0). Miso can act as an oxygen-mimetic agent in such hypoxic regions and can repair damage from-radiation-induced radicals, a process which already occurs efficiently if oxygen is present. Miso is ineffective in oxygen. Since hypoxic cells rarely exist in normal tissues the effect is tumour-specific. Lesion repair by hydrogen donation by endogenous thiols is believed to compete with oxygen fixation of lesions, so it follows that the effect of thiols as radioprotectors is also influenced by local oxygen concentrations. Thiols are ineffective in anoxia. They are also relatively ineffective at extremely high oxygen concentrations, because the balance of the competition is loaded towards fixation. However, at oxygen tensions that are close to the transition region for radiosensitivity to radio-resistance (i.e., the K value), added thiols are maximally effective and the balance can most readily be tipped one way or the other. Since oxic cells predominate in normal tissues, the radioprotection by thiols seems to be specific for normal tissue.