Role of redox cycling and activation by DT-diaphorase in the cytotoxicity of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB-1954) and its analogs

In tumor cell lines with high content of DT-diaphorase (EC 1.6.99.2), the c ytotoxicity of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB-1954) and its der ivatives is exerted through DT-diaphorase-catalyzed formation of crosslinki ng species. However, little is known about other possible mechanisms of CB- 1954 action. We have examined the toxicity of CB-1954 and its derivatives t o bovine leukemia virus-transformed lamb fibroblasts (line FLK), which poss essed moderate DT-diaphorase activity, 260 units/mg protein. The action of these compounds was accompanied by lipid peroxidation, their toxicity was d ecreased by desferrioxamine and antioxidant N,N'-diphenyI-p-phenylene diami ne (DPPD), but, in most cases, not by dicumarol, an inhibitor of DT-diaphor ase. Using multiparameter regression analysis, we have found that the toxic ity of CB-1954 derivatives as well as that of several non-alkylating nitroa romatics, increased upon the increase in their single-electron reduction po tential (E-7(1)) and octanol/water partition coefficient (P), and almost di d not depend on their reactivity towards DT-diaphorase. It seems that in ce ll lines with a moderate amount of DT-diaphorase, the toxicity of CB-1954 a nd its analogs is exerted through their redox cycling. (C) 1999 Elsevier Sc ience Ireland Ltd. All rights reserved.