VOL. 4 (1950) ABNORMALITIES IN CELL DIVISION 295 



These agents also cause visible damage to chromosomes and it is probable that the 

 inherited variations are due to change of plasmagenes or to chromosome damage which 

 might not have been visible if the affected cell had been examined. The dose of mutagenic 

 agent which is required to produce visible abnormalities will cause death in many of 

 the treated cells and the new forms arise in the cells which have received a sublethal dose. 



The tumours which arise as the result of treatment of cells with a mutagenic agent 

 are possibly derived from a normal host cell which has produced daughter cells differing 

 from the parent cell because of some accidental error or abnormality of cell division. 

 When the total number of cell divisions in the whole mammalian body is taken into 

 account these abnormalities are very infrequent. The chance of their occurrence seems 

 to be made much more probable by the presence of a carcinogenic or mutagenic agent. 



If the changes brought about by carcinogenic agents are random variations of the 

 original cells as suggested it is perhaps surprising that different tumours are so similar 

 in their morphology and biochemistry. Each tumour has its own specific characters 

 but the differences between tumours induced by carcinogenic agents are relatively 

 small. Different tumours resemble each other more closely than they resemble the tissue 

 of their origin. Thus tumours have less of the specific functions of the cell from which 

 the tumour arose and tumours have the property of producing lactic acid aerobically. 

 Of the mutations which occur in somatic cells probably many are unable to survive ; many 

 will die normally and others will be unable to withstand the attacks of defence processes 

 of the host. Of the numerous mutations which occur only those which produce cells able 

 to survive, grow, and induce the host to provide a blood supply, will become detectable 

 cancers, and for these biological processes specific characters of function and morphology 

 may be required. As the changes are induced by substances which damage the chromo- 

 some material (either directly or indirectly) and probably the genes, the chang esare 

 probably the result of loss or inactivation of genes, as it seems unlikely that a toxic 

 agent should add something to the nuclear material. Such changes would be analogous 

 to the mutations induced in Neurospora which result in the loss of ability to carry out 

 some specific chemical process. 



The biochemical mechanism which operates when radiations, nitrogen mustards 

 or carcinogenic hydrocarbons induce mutations or cancer, is still obscure. The nitrogen 

 mustards or chloroethylamines are chemically reactive and combine with many tissue 

 constituents and inactivate many enzymes, but particularly the phosphokinases and the 

 pyruvic oxidase enzyme system. In order to produce the chromosome damage and 

 inhibition of the growth of tumours in animals the aliphatic chlorethylamines must have 

 two chloroethyl groups (Boyland et al}'^) and the necessity of two reactive or polar 

 groups for chemotherapeutic action against cancer was suggested earlier (Boyland^^). 

 GoLDACRE, Loveless, and Ross^^ have suggested that the two active groups join 

 chromosome parts by cross linkage of protein or other constituents. As a result of these 

 additional cross linkages the division of chromosomes is hindered and breakages and 

 damage to the chromosomes occurs. This theory would not account for the action of 

 urethane (which seems to have no chemically reactive groups) and it is difficult to see how 

 arsenicals such as sodium arsenite could act in this way. Sulphydryl compounds are the 

 only known tissue constituents with which arsenite is known to react. As there is very 

 little cysteine or other sulphydryl compound in chromosomes (D.widson and Lavvrie") 

 combination of chromosome chains by union of sulphydryl groups through an arsenic 

 atom is unlikely to occur. It also seems improbable that X-rays would cause stable cross 

 References p. 300. 



