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.
Zeller
W J
WJ
Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg, Federal Republic of Germany.
Frühauf
S
S
Chen
G
G
Eisenbrand
G
G
Lijinsky
W
W
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D009607:Nitrosourea Compounds / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; C059884:1-nitroso-1-(2-chloroethyl)-3-(2-hydroxypropyl)urea; C059881:1-nitroso-1-(2-hydroxyethyl)-3-(2-chloroethyl)urea; C059882:1-nitroso-1-(2-hydroxypropyl)-3-(2-chloroethyl)urea; C013876:elmustine