NEW EVIDENCE ON THE MECHANISM OF RADIATION LEUKAEMOGENESIS 53 



BERENBLUM: Tliis is ail experiment which has to be done. Unfortunately, each experiment 

 involves more than a thousand mice, and we cannot do all we should like to do at once. 

 The possibility you favour has certainly to be considered. I hope I did not give the 

 impression that the evidence presented proves the other one. 



cottier: Prof. Berenblura did you consider a lowering of immune response as a con- 

 sequence of urethane administration as a possible factor in these experiments? 

 BERENBLUM: My Colleague, Dr. Trainin, is about to undertake this work, while on leave 

 abroad. 



MOLE: May I ask a question just to clarify my own mind? In Prof. Berenblum's classical 

 experiments on skin carcinogenesis initiation is a change that, once produced, persists 

 more or less indefinitely. Now here, if I understood him, initiation is the possible release 

 of a possible agent. Is this the same thing? 



BERENBLUBi: This is a very searching question. I wish I knew the answer. AU I can say is 

 that initiation persists here as weU, but it looks as if it is a different mechanism. It does 

 not persist wdtliin a living ceU. The fact that we get the same result 30 days later, or one 

 day later, after initiating action is consistent with persistence. We appear to have moved 

 from the cellular to the sub -cellular level. It is something new to us too, and we are very 

 intrigued by it. 



MOLE: May I pursue this? You refer to the fact that divided doses are more leukae- 

 mogenic than single doses and I take it you imply that they have some kind of promoting 

 action. If you accept this idea then continuing irradiation presumably will always lead 

 to a continued increase in leukaemia. 



BERENBLUM: Ycs, I agree. This is the implication. Further experiments along these lines 

 are in progress. 



UPTON: I would like to take up the point Dr. Mole raised. I tliink that one must balance 

 against initiation and promotion the killing of cells versus the effects on the host environ- 

 ment that interfere with the expression of the carcinogenic transformation. As one 

 increases the dose beyond a certain point one may weU run into this kind of inhibitory 

 effect and I dare say that fractionation would influence the survival of the cells which are 

 initiated. 



CURTIS: As to Dr. Upton's remark, we have some experiments which definitely show that 

 the incidence of leukaemia decreases with repeated doses. It faUs much below what you 

 can get at earlier stages. 



BERENBLUM: The point I want now to raise is a higlily speculative one, wliich I haven't 

 had time to discuss earlier: Whereas in our C57BL mice the urethane produced about 

 5% of leukaemia, there are reports in the literature of higher incidences of leukaemia 

 produced by urethane in SavIss mice. We did try to speculate as to how this could be 

 (see Fig. 1 p. 51). We know that if we start with C57BL mice we need both initiating 

 action (X-rays) and promoting action (urethane) to induce leukaemia. At the other 

 extreme, if we start with a strain of animals that already carries the leukaemia virus, 

 like AKR, we do not need anything at aU for leukaemia induction. Far from increasing 

 the incidence of leukaemia, X-rays actually reduce the incidence in AKR mice. We also 

 know that urethane only speeds up leukaemia development without increasing the inci- 

 dence in AKR mice. Why not postulate that Swiss mice are at an inbetween level? 

 They may already have the precursor-virus, and therefore will not require initiating 

 action. But they will need urethane to complete the leukaemogenic process. 

 ROLLER: Prof. Berenblum's speculations tempt me to speculate on his speculations. He 

 says that in C57BL mice the target-cells would be in the thymus. We know that by using 

 X-rays alone we cannot produce leukaemia. If he adds urethane, he increased the inci- 

 dence of the leukaemia; now I beUeve that with X-rays we damage the bone-marrow too, 



