Biological activity of hydroxylated chloroethylnitrosoureas.

1-Nitroso-1-(2-hydroxyethyl)-3-(2-chloroethyl)urea (Compound I) and 1-nitroso-1-(2-hydroxypropyl)-3-(2-chloroethyl)urea (Compound II) display significantly reduced antitumor activity compared to the corresponding isomeric derivatives 1-nitroso-1-(2-chloroethyl)-3-(2-hydroxyethyl) urea (Compound III) and 1-nitroso-1-(2-chloroethyl)-3-(2-hydroxypropyl) urea (Compound IV). Their low therapeutic activity is paralleled by low toxicity while mutagenicity and carcinogenicity are high. A comparative investigation of the genotoxicity of Compounds I and III using primary cultures of fetal hamster lung cells revealed an about 14-fold higher rate of DNA single-strand breaks following exposure (100 microM, 1 h) to Compound I as compared to Compound III. The rate of DNA interstrand cross-links, on the other hand, was 11-fold higher following Compound III as compared to Compound I. The results underline that the therapeutic activity of chloroethylnitrosoureas is mainly attributable to their cross-linking potential while induction of DNA single-strand breaks plays a decisive role for mutagenicity and carcinogenicity but appears not to be relevant for antineoplastic effectiveness.