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 cytotoxicity of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB-1954) and its derivatives is exerted through DT-diaphorase-catalyzed formation of crosslinking species. However, little is known about other possible mechanisms of CB-1954 action. We have examined the toxicity of CB-1954 and its derivatives to bovine leukemia virus-transformed lamb fibroblasts (line FLK), which possessed moderate DT-diaphorase activity, 260 units/mg protein. The action of these compounds was accompanied by lipid peroxidation, their toxicity was decreased by desferrioxamine and antioxidant N,N'-diphenyl-p-phenylene diamine (DPPD), but, in most cases, not by dicumarol, an inhibitor of DT-diaphorase. Using multiparameter regression analysis, we have found that the toxicity of CB-1954 derivatives as well as that of several non-alkylating nitroaromatics, increased upon the increase in their single-electron reduction potential (E(1)7) and octanol/water partition coefficient (P), and almost did not depend on their reactivity towards DT-diaphorase. It seems that in cell lines with a moderate amount of DT-diaphorase, the toxicity of CB- 1954 and its analogs is exerted through their redox cycling.
Miŝkiniene
V
V
Institute of Biochemistry, Vilnius, Lithuania.
Sergediene
E
E
Nemeikaite
A
A
Segura-Aguilar
J
J
Cenas
N
N
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001388:Aziridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000502:physiology*; D010084:Oxidation-Reduction; D051381:Rats; D012756:Sheep
D000970:Antineoplastic Agents; D001388:Aziridines; C100099:tretazicar; D016660:NAD(P)H Dehydrogenase (Quinone)