PMID: 3744944Jul 1, 1986Paper

Reductive metabolism and hypoxia-selective toxicity of nitracrine

International Journal of Radiation Oncology, Biology, Physics
W R WilsonJ C Probert

Abstract

The 1-nitroacridine nitracrine [NC,1-nitro-9-(dimethylaminopropyl-amino)acridine] is a potent hypoxia-selective cytotoxic agent in culture, but lacks activity against hypoxic tumor cells in vivo at therapeutically accessible doses. To clarify reasons for this failure in vivo the metabolism of NC was investigated in stirred suspension cultures of Chinese hamster ovary cells, in EMT-6 spheroids, and in mice. One major low molecular weight metabolite (identical to that generated by NaBH4/Pd/C reduction) was observed in hypoxic (less than 10 ppm O2) single cell suspensions, while [G-3H-acridinyl]NC formed trichloroacetic acid- and acetonitrile-insoluble macromolecular adducts (MA) at a rate seven-fold higher than in aerobic (20% O2) cultures. Formation of these adducts correlated with cytotoxicity under air or nitrogen, and hence may provide a dosimeter for NC-induced damage. Autoradiographic investigation of the distribution of MA in spheroids equilibrated with 5% O2 showed that the label was restricted to the outer cell layers rather than being localized in the hypoxic central region. Thus metabolic activation is probably too rapid, even in well-oxygenated cells, to allow adequate distribution to hypoxic microenvironments in tumo...Continue Reading

Citations

May 1, 1995·General Pharmacology·M Gniazdowski, L Szmigiero
Aug 7, 2003·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Marcelo M RossaIgor A Degterev
Aug 9, 2008·Medicinal Research Reviews·Yu Chen, Longqin Hu
Apr 1, 1992·Japanese Journal of Cancer Research : Gann·M V PapadopoulouW D Bloomer
May 1, 1996·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·I G RobertsonB D Palmer
Apr 1, 1987·International Journal of Radiation Biology and Related Studies in Physics, Chemistry, and Medicine·P B RobertsW R Wilson

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