Caffeine, aminoimidazolecarboxamide and dicoumarol, inhibitors of NAD(P)H dehydrogenase (quinone) (DT diaphorase), prevent both the cytotoxicity and DNA interstrand crosslinking produced by 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) in Walker cells.

Biochemical Pharmacology
J J RobertsR J Knox

Abstract

A form of NAD(P)H dehydrogenase (quinone) (DT diaphorase, menadione reductase (NMOR), phylloquinone reductase, quinone reductase, EC 1.6.99.2) has been isolated from Walker 256 rat carcinoma cells. This enzyme can convert 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB 1954) to a cytotoxic DNA interstrand crosslinking agent by reduction of its 4-nitro group to the corresponding hydroxylamino species (Knox et al. Biochem Pharmacol, 37: 4661-4669 and 4671-4677, 1988). 2-Phenyl-5(4)-aminoimidazole-4(5)-carboxamide and AICA [5(4)-aminoimidazole-4(5)-carboxamide] have previously been reported to be antagonists of the anti-tumour effects of CB 1954. We have shown that both these compounds are inhibitors of the above enzyme and that AICA protects against both the cytotoxicity and the formation of DNA interstrand crosslinks, produced by CB 1954 in Walker cells. Similarly, known inhibitors of NAD(P)H dehydrogenase (quinone) such as dicoumarol, also reduced the cytotoxicity and DNA-interstrand crosslinking of CB 1954 in Walker cells. Caffeine was shown to be a novel inhibitor of NAD(P)H dehydrogenase (quinone) and also elicited the above protective effects. All of the above inhibitors were also shown to potentiate the toxic effects of menadio...Continue Reading

References

Nov 15, 1986·Archives of Biochemistry and Biophysics·J E Segura-AguilarC Lind
Jun 15, 1988·Biochemical Pharmacology·A S AtallahP Hochstein
Nov 14, 1986·Biochemical and Biophysical Research Communications·J J RobertsR J Knox
Jan 15, 1972·International Journal of Cancer. Journal International Du Cancer·T A ConnorsD H Melzack
Jun 2, 1971·Nature: New Biology·B J Phillips, E J Ambrose

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Citations

Sep 1, 2005·Toxicology·Magdalene Huen Yin TangMalcolm D Tingle
Apr 23, 2004·Molecular Pharmacology·David SiegelDavid Ross

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