310 Z. M. BACQ AND P. ALEXANDER 



(1) substitution of the H in the S or N decreases the activity ; in otlier 

 words the sulphydryl and amino functions must be free. Activity is re- 

 tained if one hydrogen of the amino group is substituted by a guanidyl 

 group to give mercaptoethylguanidine (Doherty et al., 1957). This sub- 

 stitution does not change greatly the physico-chemical jDroperties of the 

 molecule, the guanidine being a strong basic group. 



(2) if the length of the carbon chain is increased beyond 3 C atoms, the 

 activity falls sharply; in other words, there is an optimal distance of 

 2 or 3 C between a strong covalent group (SH) and a basic group (NH2). 



The Oak Ridge group has perfectly understood that these facts 

 cannot be explained by anoxia or the mixed disul])hide theory, but are 

 readily interpreted by mechanisms involving free radicals. As a matter 

 of fact the views of this group are very close to ours. 



The structure which favours chelation, also favours chemical protec- 

 tion (Alexander et al., 1955). 



(f ) The phenomenon of local protection in mammals is also im- 

 portant because general effects on circulation causing anoxia are absent. 

 For instance the vaginal or the rectal epithelium is protected by local 

 application of cysteamine or cystamine (for bibliography, see Bacq and 

 Alexander, 1955). The skhi of man, rat and mice is protected locally by 

 cysteine or cysteamine injected subcutaneously in small amounts or 

 introduced in the skin by ionophoresis. Here again the difference be- 

 tween cysteamine and histamine is obvious (Radivojevitch et al., 1960) : 



(i) When very small amounts (25 fjug) of cysteamine are injected sub- 

 cutaneously into 8 days old C 57 black mice, the hair falls after irradi- 

 ation except around the injected spot; large doses do not succeed in 

 protecting the whole skin. 



(ii) Histamine does not protect locally, but if enough histamine is 

 injected subcutaneously, the whole skin is protected apparently because 

 the reduced blood pressure and slow circulation have induced a suffici- 

 ently deep anoxia. 



Thus, as far as cysteamine in mammals is concerned, it seems that 

 neither the mixed disulphide hypothesis, nor anoxia can explain the 

 observed facts. We believe that one or several mechanisms involving 

 free radicals are much more likely to l)e resjionsible for the protective 

 abiUty of cysteamine in mammals. 



Protection by competitive removal of free radicals and by rejDair is 

 possible in addition to direct energy transfer as observed in model 

 systems. The repair mechanism is likely to play an important part, 

 since it ])rovides an explanation why protection is more marked in 

 aerated cells. Once the radiosensitivity has been reduced by anoxia, 

 chemical protection is in general much less marked. In 1955 we tenta- 



