MODIFICATIONS OF DNA BY DIFFERENT HALOETHYLNITROSOUREAS

Abstract

The modification of DNA [calf thymus] by the haloethylnitrosoureas [cancer therapy agents] 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 2nd reaction of the haloethyl group with the opposite DNA strand. 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. DNA was reacted with the following compounds: N,N''-bis(2-chloroethyl)-N-nitrosourea (NSC 409,962); N-(2-chloroethyl)-N''-cyclohexyl-N-nitrosourea (NSC 79,037); N-(2-chloroethyl)-N''-(2,6-dihydroxycyclohexyl)-N-nitrosourea (NSC 264,395); N-(2-chloroethyl)-N-nitrosourea (NSC 47,547) and N-(2-fluoroethyl)-N''-cyclohexyl-N-nitrosourea (NSC 87,974). Reacted DNA was depurinated and the distribution of guanine derivatives was obtained by high-pressure liquid chromatography. The distribution of products obtained is markedly influenced by the chemical structure of the nitrosourea. Differences are noted in the relative amounts of 6- vs. 7-substituted guanines, in the amount of hydroxyethylation vs. 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.