The cytotoxicity of chlorambucil and its associated effects on NAD metabolism

Abstract

Chlorambucil has been reacted with two strains of Yoshida ascites sarcoma cells in vitro and in vivo, and the resultant changes in NAD and NAD-metabolising enzymes related to the quantitative cytotoxicity of the drug at the various doses used. There was no change in the NAD content at any dose up to the LD 100 figure in vivo or in vitro, though supra-lethal concentrations did produce a fall in NAD content in vitro. Curative doses of drug led to increase in the specific activities of NAD glycohydrolase and ATP:NMN adenylyl transferase in vivo, but these were not reflected in changes in the NAD level. Supra-lethal concentrations of the drug produced only small decreases in the levels of these enzymes in vitro. It is concluded that the cytostatic effects of chlorambucil are not mediated through an effect on the intracellular NAD concentration, though at supra-lethal concentrations of the drug a loss of NAD does occur, which may be attributed to non-specific damage to the plasma membrane.