Alkylating agents.

The mechanisms of action of alkylating agents may be summarized as follows: (1) replacement of H atoms by alkyl radicals, (2) combination with sulfhydryl, carboxyl, phosphate, and amino groups, (3) combination with purines of deoxyguanylic acid, guanine of DNA, P of nucleotides, N of histidine ring, (4) crosslinking of DNA strands and proteins; inhibition of DNA synthesis, protein syn­ thesis, ribonuclease, phosphorylation of ATP, glycolysis and respiration, mitosis, (5) mutations, (6) chromosome breaks and bridges, and (7) changes in cell walls. Although the alkylating agents differ in their action, they are all capable of replacing hydrogen atoms by alkyl radicals (aliphatic hydrocarbons deprived of an H atom) (272). Cyclic imines and carbonium and sulfonium ions are formed in tissue fluids and react rapidly with cellular constituents, particularly sulfhydryl groups, carboxylic acids, phosphates, and amines. As chemical groups are modified they may be deleted from amino acids, thereby changing the normal sequence of polypeptide chains. The nitrogen of the histidine ring, purines of deoxyguanylic acids, guanine of DNA, and phosphate groups of nucleotides react easily with the alkylating agents. Through these reactions, DNA synthesis and ribonuclease acti­ vity are inhibited and cross-linking of DNA strands and protein develops, in­ activating the functions of DNA and causing mutations and chromosome aber­ rations (3, 4). A number of enzymes are inhibited, resulting in decreased phosphorylation, glycolysis, respiration, protein synthesis, and cell proliferation. The cytotoxic actions of alkylating agents are therefore relative crude, with multiple sites affected.