96 



One might expect that many of the biochemical effects of nitrogen mustard would 

 resemble those of X-rays, and for some types of experiments, the nitrogen 

 mustard might be more useful than X-rays. 



KAPLAN: In that connection, I do not know how your doses compare 

 with the sublethal but toxic doses of mustard that we have used in mice. In our 

 experiments, they produced essentially no decrease in thymic weight. Compar- 

 able doses of whole-body X radiation, in terms of lethality, cause a decrease in 

 thymic weight to perhaps 15 or 20 percent of normal. So that this apparently 

 "radiomimetic" substance is not always radiomimetic. It is interesting that it 

 should produce a similar biochemical effect in the thymus of rats. It would be 

 interesting to check to see whether the rat's thymus is equally sensitive to the 

 drug in terms of weight response. 



DUBOIS: That is a point worthy of mention. Lethal doses of the nitro- 

 gen mustard produced effects equivalent to, or resembling, those obtained by 

 200 r X radiation. 



sons 



BENNETT: I should like to ask -- I suppose there are technical rea- 

 why the spleen and thymus are studied and only seldom the bone marrow? 



DUBOIS: The spleen and thymus are used as examples of radiosensi- 

 tive tissues. In many types of experiments the amount of tissue required is a 

 factor that limits the choice when animals such as the rat or the mouse are 

 used. 



Now to proceed with our main discussion. The data in Table 1 show 

 that carbohydrate metabolism in the liver is not interrupted by doses of nitrogen 

 mustard that will produce a marked increase in citrate synthesis. The oxidation 

 of pyruvate and fumarate by liver homogenates prepared from rats given 1 mg. 

 per kg. (a lethal dose) of methyl-bis ((3-chloroethyl) amine takes place at a nor- 

 mal rate. Nor is the oxidation of acetate or pyruvate or the formation of aceto- 

 acetate affected. The absence of effects on these reactions resembles the lack 

 of effects following doses of whole-body X irradiation on tissue respiration. By 

 measurements of specific enzyme concentrations, it is quite well established 

 that the activity of cytochrome oxidase, succinic dehydrogenase, and of malic 

 dehydrogenase is not inhibited or increased by lethal doses of radiation in most 

 tissues, including spleen and thymus. There have been reports of the activity of 



succinic dehydrogenase being decreased in 

 the spleen after irradiation, but this amount- 

 ed to a decrease of only about 25 percent 

 after as much as 800 r. A great deal of fur- 

 ther work has to be done, especially on tis- 

 sues which are sensitive to radiation, in 

 which systematic investigations of the en- 

 zyme systems are conducted. 



One of the groups of enzymes which 

 does show a change when specific assays are 

 used is adenosine triphosphatase (8). The 

 data in Figure 3 show the results of adeno- 

 sine triphosphatase assays on spleens of ir- 

 radiated rats. Twenty-five r produces a re- 

 sponse and 50, 100, 200 and 400 r produce 

 further increases in enzyme activity. The 

 maximum was about 2.5 to 3 times the nor- 

 mal activity in this tissue. This is not an in- 



R0ENT6ENS 



13 5 7 10 



DAYS AFTER X-RAY 



Figure 3. Adenosine triphosphatase ac- 

 tivity of the spleens of rats at intervals 

 after various exposures to total-body X 

 radiations. (This chart appeared in the 

 paper by K.P.DuBois and D. F.Petersen, 

 American Journ. of Physio. 176,282-286 

 1954). 



