Nature and biological significance of DNA modification by the haloethylnitrosoureas.

The haloethylnitrosoureas are both successful antitumour agents and laboratory carcinogens. A growing body of evidence suggests that their biological activities result from DNA modification. By decomposing in different ways, the haloethylnitrosoureas generate intermediates that can introduce either hydroxyethyl or haloethyl groups into DNA. One hydroxyethyl derivative, O6-hydroxyethylguanine, may be responsible for at least some of the carcinogenicity of these compounds. Haloethyl derivatives lead to cross-linked structures which may be cytotoxic. Two such cross-links, 1-(3-deoxycytidyl)-2-(1-deoxyguanosinyl)ethane (dCydCH2CH2dGuo) and 1,2-bis(7-guanyl)ethane (GuaCH2CH2Gua), have been isolated from DNA that has been reacted with haloethylnitrosoureas. Various DNA repair mechanisms, including O6-alkylguanine-DNA alkyltransferase, evidently play a role in modulating both the carcinogenic and cytotoxic actions of these agents.