Effects of nitrogen mustard and cyclophosphamide upon the synthesis of DNA in vivo and in cell-free preparations.

and concentrations of the nitrogen mustard, it was possible to inhibit the synthesis of DNA more than that of RNA and to inhibit synthesis in a sensitive tumor without inhibiting synthesis in a bilaterally growing resistant tumor. Other studies (23) showed that multidose treatment of hamsters bearing plasmacytomas with cyclophosphamide [2-[bis(2chloroethyl)amino]-2H-1,3,2-oxazaphosphorinane 2-oxide] caused decreases in the activity of DNA nucleotidyltransferase and of thymidylate kinase of soluble cell fractions prepared from the plasmacytomas, but that a single dose of cyclophos phamide given 2 hours before killing the animal caused an increase of the DNA nucleotidyltransferase activity. These results provoked the questions whether the observed decreased synthesis of DNA in vivo and the decreased nucleotidykrans ferase activity were the cumulative effects of multiple doses of the agents, whether similar effects would be observed at longer intervals after the administration of single doses of the drugs, and whether decreased nucleotidyltransferase activity is a pri mary or secondary effect of the drug. In pursuit of answers to these questions, we have now performed experiments to: (a) determine the relationship between the interval after admin istering a single dose of nitrogen mustard or cyclophosphamide and the effect upon the synthesis of nucleic acids in vivo, (b) determine the effects of treatment of cell-free preparations from plasmacytomas with nitrogen mustard upon the DNA nucleotidyltransferase activity, (c) determine the effects of treatment of DNA with nitrogen mustard in vitro upon the priming activity of the DNA for the DNA nucleotidyltrans ferase system, and (d) compare the effects of in vivo treatment with cyclophosphamide upon the in vivo synthesis of DNA by plasmacytomas and upon the DNA nucleotidyltransferase activity of a cell-free preparation from the same plasmacy tomas.