Effects of Nitrogen Mustard and Cyclophosphamide upon the Synthesis of DNA in Vivo and in Cell-free Preparations

Summary Single doses of nitrogen mustard or cyclophosphamide caused regression of plasmacytomas in hamsters and decreases in the rate of synthesis of DNA and RNA by the tumors. Maximum inhibition of synthesis did not occur immediately following the administration of the agent but was observable 24–48 hours later. This inhibition was accompanied by a decrease in DNA nucleotidyltransferase activity of crude cell-free supernatant fractions prepared from the treated tumors. The concentrations of nitrogen mustard required for in vitro deactivation of the crude DNA nucleotidyltransferase and for in vitro deactivation of commercial salmon sperm DNA as a primer for this system were much greater than those that would be present in hamsters following the administration of therapeutically effective doses. It was concluded that neither the direct deactivation of the DNA nucleotidyltransferase nor gross interference with the primer activity of DNA is the cause of the observed therapeutic effect upon the tumor or the decrease of synthesis of DNA in vivo . Transient inhibition of growth and of synthesis of DNA and RNA by drug-resistant tumors was also observed. It is not presently known whether the resumption of growth and synthesis of nucleic acids is the result of repair of damage and recovery by the cells or of killing and elimination of the cells of the tumor that are most sensitive to the agent. It is evident, however, that inhibition of the synthesis of DNA and RNA by a tumor during the first 48 hours following administration of nitrogen mustard or cyclophosphamide cannot be considered to be indicative that a favorable therapeutic effect of the agent has been accomplished.