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The radioprotective effect of eight thiol compounds with pK-values of their thiol groups varying from 8'5-10'8 was tested on isolated cells in vitro. The influence of variations in pH of the incubation medium between 6-3 and 83 was investigated. The ability of the cells to form colonies was used as the criterion for survival.By comparing the protection affected by different concentrations of the various compounds it was found that a good correlation existed between the degree of radio-protection and the thiolate concentration in the medium. This correlation was also found to be present under anoxic conditions. It was concluded that the increase of the radio-protective activity of the thiol compounds, caused by an increase of either concentration, pH or temperature, can be explained by an increase of the amount of thiol compound present inside the cell. The differences in radio-protective activity of the various compounds cannot be explained by differences in cellular uptake.The thiol compounds with a pK-value lower than 10 appeared to be very toxic at concentrations between 01 and 2-0 mM, but not at concentrations lower than 0-1 mM and between 2 to c. 100 mM. This striking toxicity could be prevented by incubation under anoxic conditions, by a decrease of the pH to 63, by addition of an excess of another thiol compound or of KCN, but not by addition of NaS,0 3 . The toxic action of the thiol compounds at these concentrations seems to be caused by an irreversible intracellular reaction of a specific oxidation product of these compounds with some cellular constituant.

In tissue culture, protection against X-irradiation by a number of cysteamine derivatives was studied and the results were compared with data obtained in mice. Compounds with a covered SH group, like WR 638, cysteamine phosphate, WR 2721, and AE 48527, showed practically no protection when dissolved in tissue-culture medium, but developed a protective activity when dissolved in rat blood. Thiol measurements demonstrated that in rat blood the compounds were partly hydrolysed to thiols. C511 was also hydrolysed in culture medium and was slightly less effective than cysteamine in culture medium. Cysteamine phosphate was hydrolsed more easily than cysteamine sulphate and the protective activity in rat blood was better. WR 2721 was also partly hydrolysed in rat blood. The in vitro protection of this compound was disappointing when compared with results in vivo. Its SH form (WR 1065) also showed less protection than expected from in vivo experiments. Thus, the little protection by WR 2721 in vitro in rat blood is not only due to its incomplete conversion into its thiol. Longer incubation times and the use of rat blood as a solvent brought the protective activity of WR 1065 almost up to the level of cysteamine. This may indicate that WR 1065 penetrates the cells poorly. WR 1065 was the only compound we studied whose protective activity in vitro was improved appreciably by dissolving it in rat plasma.