THE INHIBITION OF DNA SYNTHESIS BY IRRADIATION 



rate of synthesis increases rapidly up to about 24 or 27 hours after hepa- 

 tectomy. A fast rate is maintained for some hours ; at about 42 hours, 

 however, the rate of synthesis and the rate of mitosis are lower than before, 

 but remain at a fairly constant level. During this later period, the tissue 

 can probably be regarded as an ordinary growing tissue containing all 

 stages of the mitotic cycle in an established proportion. 



In the following experiments rate of synthesis has usually been measured 

 by uptake of ^^P, but many confirmatory experiments have been done with 

 glycine ^^C as marker. If irradiation is given at 12 hours, no cells will yet 

 be in the synthetic stage. It is easy to show the sensitivity of DNA synthesis 

 to irradiation at 12 hours, since 450 r will delay synthesis for many hours 

 and some delaying action can be seen with as small a dose as 150r. This 

 small dose will also cause a delay of a few hours in the appearance of the first 

 mitoses and 450 r will cause a longer delay (9 hours). This early-stage 

 irradiation with small doses can also cause chromosome breakage ; Roller 

 has seen about 10 per cent of breaks about 15 hours after irradiation with 

 150r, in the first mitoses to appear ; about 20 hours after 450 r he has 

 found chromosome breakage in up to 100 per cent of the first dividing cells. 



Twelve or fifteen hours after irradiation (that is, 24-27 hours after the 

 partial hepatectomy) all these effects are very apparent. Mitosis is sup- 

 pressed and the DNx\ synthesis, which is very rapid in the controls, is 

 scarcely beginning. The period from about 15 to about 24 hours after the 

 hepatectomy is one of DNA synthesis, but still without mitosis ; this begins 

 at about 24 hours but is much more active at 27 or 30 hours, when from 

 3 per cent to 6 or even 10 per cent of cells may be found to be in mitosis. 

 It is once more very easy to show, thus confirming other authors, that 

 irradiation with doses of 450 r has no immediate effect on DNA synthesis 

 if delivered during this period of active synthesis. It must be emphasized, 

 however, that mitosis can still be greatly delayed by this irradiation and it 

 seems that we must believe that inhibition of some other mechanism than 

 DNA synthesis must here be the cause of the temporary inhibition of mitosis. 



If we consider the case of a growing tissue, containing cells in all stages 

 of mitosis, we can see that the 50 per cent inhibition of deoxynucleic acid 

 synthesis produced by fairly large doses of X-rays could not be produced 

 if only the cells in the pre-synthetic stage were aflfected. The 50 per cent 

 inhibition is an immediate effect, whereas some hours must elapse to allow 

 the pre-synthesis inhibition to demonstrate itself at all strikingly. An 

 immediately visible inhibition must be due to an immediate inhibition in 

 the synthetic period. Lajtha has described experiments in which this 

 inhibition can be brought about by 5,000 r. In a confirmatory experiment 

 (only one so far) we have found that 2,200 r will cause an immediate 50 per 

 cent inhibition of DNA synthesis during the synthetic period ; this is a 

 dose sufficient to cause regression in at least 50 per cent of various implanted 

 tumours and would probably cause the death of the liver lobe. The effect 

 of 450 r on DNA synthesis is temporary only ; the effect of 2,200 r is probably 

 irreversible {see Table I). When X-radiation is acting on a dividing tissue 

 with cells in all stages (46 hours), 450 r is not sufficient to produce an immedi- 

 ate reduction in rate of DNA synthesis, whereas 2,200 r is sufficient. If on 

 the other hand, the period from 9-12 hours after the irradiation is chosen 



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