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More Than Additive Toxicity of the Combination of 1-Methyl-1-nitrosourea Plus 1,3-Bis(2-chloroethyl)-1-nitrosourea in the Rat

Institute of Toxicology and Chemotherapy [W. J. Z., M. R. B., T. H.], and Department of Biostatistics [E. W.], German Cancer Research Center, Im Neuenheimer Feld 280, D-6900 Heidelberg, Federal Republic of Germany

The combination toxicity index of 1-methyl-1-nitrosourea plus 1,3-bis(2-chloroethyl)-1-nitrosourea determined in the rat was 0.32. This overadditive combination toxicity appears mainly to be due to severe damage of the intestinal mucosa as diagnosed by histological examination and to damage of pluripotent stem cells in the bone marrow as could be assessed by the spleen colony technique. The molar ratio of 1-methyl-1-nitrosourea to 1,3-bis(2-chloroethyl)-1-nitrosourea resulting in maximum mortality was about 6. Concomitantly measured DNA interstrand cross-linking in bone marrow cells revealed a slight increase in DNA interstrand cross-linking following both drugs compared to 1,3-bis(2-chloroethyl)-1-nitrosourea alone.

Received 3/18/85. Revised 12/ 3/85. Accepted 12/12/85.