Modifications of DNA by different haloethylnitrosoureas

The modification of DNA by the haloethylnitrosoureas is probably responsible for their antitumor activity. A current hypothesis relates this cytotoxic action to the transfer of haloethyl groups from the nitrosourea to DNA followed by a second reaction of the haloethyl group with the opposite DNA strand. However, other modifications besides interstrand cross-links are introduced into DNA, raising the question whether the choice of the particular nitrosourea could affect the distribution of DNA modifications in a way which would maximize cytotoxic activity. To investigate this point, DNA was reacted with the following compounds: N,N'-bis(2-chloroethyl)-N-nitrosourea (NSC 409962); N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea (NSC 79037); N-(2-chloroethyl N'-(2,6-dihydroxycyclohexyl)-N-nitrosourea (NsC 264395); N-(2-chloroethyl)-N-nitrosourea (NSC 47547); and N-(2-fluoroethyl(-N'-cyclohexyl-N-nitrosourea (NSC 87974). Reacted DNA was depurinated, and the distribution of guanine derivatives was obtained by high-pressure liquid chromatography. These studies have shown that the distribution of products obtained is markedly influenced by the chemical structure of the nitrosourea. Differences are noted in the relative amounts of 6- versus 7-substituted guanines, in the amount of hydroxyethylation versus haloethylation, and in the amount of diguanylethane formation. Thus, it may be possible to modulate the biological effect obtained from a nitrosourea by changing its molecular structure.