Carcinogenicity of 1-(4-Amino-2-Methylpyrimidine-5-yl)-Methyl-3-(2-Chloroethyl)-3-Nitrosoureahydrochloride and Three Related N-Nitroso Derivatives following Repeated Intravenous Administration to Male Wistar Rats

Abstract

Long-term toxic evaluation of l-(4-amino-2-methylpyrimidine-5-yl)-methyl-3-(2-chloroethyl)-3-nitrosoureahydrochloride (ACNU), 1 -(2-chloroethyl)-1 -nitroso-3-(methylene-2-pyridylium)-urea-hydrochlo-ride (CNMPU), 1-(2-chloroethyl)-l-nitroso-3-(4-thiomorpholino)-urea (CNTMU) and 4-[N-(2-chloro-ethyl)-N-nitrosocarbamoyl]-morpholine (CNCM) which were administered each at five dosages, adapted to the clinical situation, revealed significantly increased tumor risks for the first three agents in the lung and the adrenal gland. Additionally, CNTMU and ACNU induced a significant rise in the tumor load of the neurogenic tissue; the latter compound, being in clinical use, was associated with a significantly increased number of mammary tumors as well. CNCM, however, did not exhibit significantly elevated carcinogenic activity, although the overall tumor load was up to 2.4-fold increased compared to controls. The results indicate no advantage of the newly developed ACNU with respect to its inherent carcinogenic risk as compared to clinically established 2-chloroethyl-N-nitroso derivatives.