The binding of 1-(2-hydroxyethyl)-1-nitrosourea to DNA in vitro and to DNA of thymus and marrow in C57BL mice in vivo

Abstract

To investigate the hypothesis that the similarity of dose-response curves for induction of thymic lymphoma in C57BL mice was due to similar DNA alkylation profiles for 1-ethyl-1-nitrosourea (ENU) and 1-(2-hydroxyethyl)-1-nitrosourea (HNU), we measured the reaction of the two agents with DNA in vitro and in target tissues in vivo. At equimolar doses, alkylation of DNA by HNU was about 20% greater than that by ENU in vitro. As a percentage of total DNA-bound alkyl groups, relative reaction at a minor groove site (3 of adenine) was similar for the two agents, but HNU caused greater relative alkylation at the major groove sites, O 6 and N-7 of guanine. At equi-oncogenic doses, alkylation at the O 6 of guanine in liver and thymus was similar for both agents, but O 6-alkylguanine formation in bone marrow by HNU was almost twice that by ENU. Because alkylation at O 6 of guanine has previously been shown to be a key procarcinogenic lesion in this system, these findings suggest the thymus, rather than the marrow as a primary target for tumor induction by these agents, although involvement of marrow alkylation cannot be ruled out.