On the mechanism of action of the alkylating agents. I. Interaction of alkylating agents with nucleic acids.

The incorporation of isotopic ethylene-C1Mmino-s-triazine (TEM), Myleran, chlorambucil, and sulfur mustard into the DNA fraction of regenerating liver and of various mouse ascites lymphomas was measured. The in vivo incorporation of these alkylating agents was estimated to be of the order of 1 mole of drug per mole of DNA polymer. Results obtained by several different methods of isolation of DNA from in vivo-treated tissues failed to show marked differences in the amounts of isotope coupled to DNA. No correlation was apparent between the susceptibility of the various tumors and the relative amounts of isotope incorporated into tumor DNA fractions. Pretreatment of tumor with nonlabeled triethylene melamine (TEM) failed to alter incorporation patterns for labeled TEM. It was concluded that attack on the DNA itself does not necessarily represent the mechanism of action by which the alkylating agents exert their cytostatic or cytotoxic effects.