296 E. BOYLAND VOL. 4 {1950) 



linkages between chromosome parts to be formed. The current theory of the action of 

 radiations on cells is that they oxidize sulphydryl groups through the production of 

 peroxide or other oxidizing agent within the cells. They could therefore unite peptide 

 chains by conversion of sulphydryl groups to the disulphide forms. The low concen- 

 tration of cysteine in the chromosomes which was suggested as a difficulty in the theory 

 as applied to the action of arsenicals would also apply to X-rays. A linkage through 

 arsenic might, however, be more stable than a disulphide link which would probably 

 be reduced in processes of cell metabolism. This hypothesis of cross linkage within 

 chromosomes being the cause of abnormalities may be of value in investigating the 

 action of drugs on tumour cells, but it is possibly of no more value than the knowledge 

 that in the chloroethylamine series and other compounds two active groups are required 

 for the biological actions considered. 



The hypothesis which the author put forward (Boyland^^) postulates that the 

 effects of these substances are due to inhibition of enzymes, particularly the phospho- 

 kinases or enzymes involving oxidative phosphorylations necessary for production and 

 metabolism of the nucleic acid required for the maintenance of normal chromosomes 

 and genes. Since then Barron, Dickman, and Singer^^ have shown that phospho- 

 glyceraldehyde dehydrogenase is particularly sensitive to the action of X-rays, and 

 Meyerhof and Wilson^" have described the inhibition of hexokinase and phospho- 

 hexokinase with phenyl urethane. 



Investigations carried out during the war showed that two enzyme systems were 

 particularly sensitive to the poisoning action of vesicants. Of the phosphokinases, 

 hexokinase was first shown by Dixon and Needham^^ to be inhibited by low concentra- 

 tions of mustard gas and nitrogen mustard. Later Cori and his co-workers^^ found 

 that phosphokinases in general are inhibited by vesicants. Peters, Sinclair, and 

 Thompson^^ found that the arsenical vesicant, lewisite and other vesicants inhibit the 

 pyruvic oxidase system. The known phosphate transferring enzymes are concerned with 

 the building up of energy rich phosphate bonds in phosphoric anhydrides and acylphos- 

 phates. Enzymes of this type must be concerned in the biosynthesis of the nucleotides 

 and nucleic acids. Although we know very little of the specific phosphokinases involved 

 in nucleic acid synthesis, the fact that all known phosphokinases are easily inhibited 

 by sulphur mustard and nitrogen mustards would suggest that nucleic acid synthesis 

 should be inhibited by these substances. The synthesis of proteins may also involve 

 phosphorylation of the terminal carboxyl group of a peptide chain and reaction of the 

 resulting acyl phosphate with a fresh amino acid molecule to give a new peptide link 

 and liberate phosphate. A model for this reaction is the formation of glutamine from 

 phosphoryl glutamic acid and ammonia (Speck^*, Elliot^^). The enzymes concerned 

 with nucleic acid and protein synthesis need investigation and for this the mitotic poi- 

 sons may be useful tools. 



The substances which induce mitotic abnormalities differ greatly in their apparent 

 chemical reactivity. The aliphatic nitrogen mustards are very reactive substances, the 

 aromatic chloroethylamines react slowly, but the aromatic carcinogenic hydrocarbons 

 are rather inert. The French theoretical chemists Daudel, Pullman and then associates 

 (Daudel^^) have shown that the carcinogenic hydrocarbons have regions, known as the 

 K regions, in which there is high electron density, which in the majority of the carcino- 

 genic hydrocarbons includes an activated phenanthrene double bond. The activation 

 is enhanced by substituents such as benzene rings or methyl groups (which repel elec- 

 Rejerences p. 300. 



