542 L. G. LAJTHA 



IV. The Analysis of the Mechanism of Radiation 

 Effect on DNA Synthesis 



As has been pointed out in Section II and in more detail elsewhere, 71 de- 

 termination of a mere specific radioactivity is a poor measure of DNA syn- 

 thesis as population changes and cell cycle changes may be overlooked. For 

 accurate analysis, work at the cellular level is required. 



The first important step in this direction was the elegant work of Howard 

 and Pelc 6 who in their autoradiographic study of bean root cells (Viciafaba) 

 first established the concept of the cell cycle in respect of DNA synthesis 

 (illustrated in Fig. 1) and have shown that moderate doses of radiation 

 decrease the proportion of cells synthesizing DNA. Their observations were 

 confirmed in human bone marrow cells in vitro. 7 They also have shown that 

 within the range of 35-200 r. the depression in the proportion of DNA syn- 

 thesizing cells is about the same (30-40 per cent), but cells which were in 

 the process of synthesis at the time of irradiation remained unaffected by 

 these doses. 72 The importance of this observation was the establishment of 

 the concept of differential sensitivity in terms of DNA synthesis of cells in 

 different parts of their intermitotic cycle. It was this work which gave 

 impetus to studies on regenerating liver (see Section III, 3) which, being a 

 nearly synchronous population of cells, lent itself for the study of the pre- 

 synthetic and synthetic periods. Work with regenerating liver also confirmed 

 the findings of Howard and Pelc, and thus the concept was established 

 that relatively small doses of radiation (50-150 r.) delivered before the 

 beginning of the period of DNA synthesis, can delay the onset of synthesis, 

 whereas once synthesis has begun much larger doses are required to inter- 

 fere significantly with the process (> 1000 r.). 



The nature of this "Gi depression" (as the effect on the presynthetic 

 period was called) was extensively investigated in human bone marrow 

 cells in vitro. 62 The conclusion from this work was that small doses (100- 

 200 r.) of radiation slow down the progress of cells through the presynthetic 

 period (Gi period) with a consequent slower feed into, and depopulation of, 

 the synthetic period (S period) which is unaffected by these doses. It was 

 suggested that there is an indication in the cells for "a system connected 

 w T ith but not identical with DNA synthesis (? trigger mechanism) which is 

 more radiosensitive than the process of DNA synthesis." In this respect 

 the finding of Potter's group is of particular interest : thymidine and thy- 

 midylic kinases — enzymes necessary for DNA synthesis, and which are 

 present in regenerating liver at about 18 hours after partial hepatectomy 

 (i.e. at the end of the Gi period) — are markedly reduced after 375 r. irradia- 



71 L. G. Lajtha, Nature 181, 1609 (1958). 



72 S. R. Pelc and A. Howard, Radiation Research 3, 135 (1955). 



