NEW EVIDENCE ON THE MECHANISM OF RADIATION LEUKAEMOGENESIS 43 



we decided to explore the possibility of radiation and uretliane having an 

 initiation-promotion relationship. This was tested by the "reversal" type of 

 experiment, mentioned above. 



Using 450 r, in divided doses of 90 r at 5-day intervals, for total-body 

 radiation, and 100 mg, in divided doses of 20 mg at 5-day intervals, for 

 intraperitoneal injections of urethane, the following results were obtained 

 when tested in C57BL/6 mice (see Table I) : (i) confirmation of the results of 

 Kawamoto et al., that radiation leukaemogenesis, in a low-leukaemia strain of 

 mice, is augmented by simultaneous administration of urethane, and (ii) a 

 similar augmentation observed when the urethane treatment is begun 2 weeks 

 after completion of the radiation treatment, hut not ivhen the sequence is 

 reversed (Berenblum and Trainin, 1960, 1961a). (The "leukaemias" produced 

 were essentially thymic lymphomas, which tended, in some cases only, to be 

 accompanied later by a blood picture of lymphatic leukaemia.) 



Table I. Promoting action of urethane in radiation leukaemogenesis in C57BL/6 



m,ice 



Treatnientf Incidence of leukaemia 



f Radiation: 90 r X 5, at 5-day intervals = 450 r. 

 Urethane treatment: 20 mg x 5, at 5-day intervals = 100 mg, injected intraperitone- 

 ally. 

 Interval between completion of one treatment and commencement of the other: 2 weeks. 



Though the results supported a two-stage mechanism for leukaemogenesis, 

 the experimental conditions were obviously not ideal, since the radiation, which 

 was intended to serve as initiating factor only, was by itself highly leukae- 

 mogenic. Experiments were then performed using single irradiations, at 

 different dose levels, instead of divided doses, in the hope that a suitable 

 range might be found where leukaemia failed to develop by initiation alone or 

 by promotion alone, but did develop by initiation followed by promotion. 

 The results (see Table II) suggest that such an experimental set-up is possible, 

 though further refinements are needed to reach the ideal conditions. 



Yet another possibility had to be considered, before accepting the results 

 as evidence of a two-stage mechanism. It seemed rather surprising that 

 urethane, an initiator for skin carcinogenesis, should act as a promoter for 

 leukaemogenesis. Could it be that urethane did not act as promoter in the 



