Potentiation of CB 1954 cytotoxicity by reduced pyridine nucleotides in human tumour cells by stimulation of DT diaphorase activity.
The toxicity of CB 1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide] towards human cells was greatly enhanced by NADH (when foetal calf serum was present in the culture medium) and by nicotinamide riboside (reduced) (NRH), but not by nicotinate riboside (reduced). Co-treatment of human cells with CB 1954 and NADH resulted in the formation of crosslinks in their DNA. The toxicity produced by other DNA crosslinking agents was unaffected by reduced nicotinamide compounds. When caffeine was included in the medium, a reduction in the cytotoxicity of CB 1954 occurred. The toxicity experienced by human cell lines after exposure to CB 1954 and NADH was proportional to their levels of the enzyme DT diaphorase NAD(P)H dehydrogenase (quinone), EC 1.6.99.2. It is concluded that NRH, which we have shown to be a co-factor for rat DT diaphorase (Friedlos et al., Biochem Pharmacol 44: 25-31, 1992), is generated from NADH by enzymes in foetal calf serum, and stimulates the activity of human DT diaphorase towards CB 1954.
Friedlos
F
F
Molecular Pharmacology Unit, Institute of Cancer Research, Sutton, Surrey, U.K.
Biggs
P J
PJ
Abrahamson
J A
JA
Knox
R J
RJ
D000970:Antineoplastic Agents / Q000633:toxicity*; D001388:Aziridines / Q000378:metabolism / Q000633:toxicity*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D007700:Kinetics; D009243:NAD / Q000378:metabolism / Q000494:pharmacology*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D011726:Pyridinium Compounds; D012263:Ribonucleosides / Q000494:pharmacology*; D013268:Stimulation, Chemical; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001388:Aziridines; D004273:DNA, Neoplasm; D011726:Pyridinium Compounds; D012263:Ribonucleosides; C018613:nicotinamide-beta-riboside; D009243:NAD; C030285:nicotinic acid ribonucleoside; D009536:Niacinamide; C100099:tretazicar; D016660:NAD(P)H Dehydrogenase (Quinone)