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Title: Protection against SR 4233 (tirapazamine) aerobic cytotoxicity by the metal chelators desferrioxamine and tiron

Abstract

Metal chelating agents and antioxidants were evaluated as potential protectors against aerobic SR 4233 cytotoxicity in Chinese hamster V79 cells. The differential protection of aerobic and hypoxic cells by two metal chelators, desferrrioxamine and Tiron, is discussed in the context of their potential use in the on-going clinical trials with SR 4233. Cytotoxicity was evaluated using clonogenic assay. SR 4233 exposure was done in glass flasks as a function of time either alone or in the presence of the following agents: superoxide dismutase, catalase, 5,5-dimethyl-1-pyrroline, Trolox, ICRF-187, desferrioxamine, Tiron (1,2-dihydroxybenzene-3,5-disulfonate), and ascorbic acid. Experiments done under hypoxic conditions were carried out in specially designed glass flasks that were gassed with humidified nitrogen/carbon dioxide mixture and with a side-arm reservoir from which SR 4233 was added to cell media after hypoxia was obtained. Electron paramagnetic resonance studies were also performed. Electron paramagnetic resonance and spectrophotometry experiments suggest that under aerobic conditions SR 4233 undergoes futile redox cycling to produce superoxide. Treatment of cells during aerobic exposure to SR 4233 with the enzymes superoxide dismutase and catalase, the spin trapping agent DMPO, the water-soluble vitamin E analog Trolox, and the metal chelator ICRF-187 provided little or no protection against aerobic SR 4233more » cytotoxicity. However, two other metal chelators, desferrioxamine and Tiron afforded significant protection against minimal protection to hypoxic cells treated with SR 4233. One potential mechanism of aerobic cytotoxicity is redox cycling of SR 4233 with molecular oxygen resulting in several potentially toxic oxidative species that overburden the intrinsic intracellular detoxification systems such as superoxide dismutase, catalase, and glutathione peroxidase. 23 refs., 4 figs., 1 tab.« less

Authors:
; ;  [1]
  1. National Cancer Institute, Bethesda, MD (United States); and others
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
96066
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 30; Journal Issue: 4; Other Information: PBD: 15 Nov 1994
Country of Publication:
United States
Language:
English
Subject:
56 BIOLOGY AND MEDICINE, APPLIED STUDIES; CHELATING AGENTS; RESPONSE MODIFYING FACTORS; TIRON; ANTIMITOTIC DRUGS; RADIOSENSITIVITY EFFECTS; AEROBIC CONDITIONS; ANTIOXIDANTS; DETOXIFICATION; ENZYMES; SPECTROPHOTOMETRY; SUPEROXIDE DISMUTASE; VITAMIN E; ANOXIA

Citation Formats

Herscher, L L, Krishna, M C, and Cook, J A. Protection against SR 4233 (tirapazamine) aerobic cytotoxicity by the metal chelators desferrioxamine and tiron. United States: N. p., 1994. Web. doi:10.1016/0360-3016(94)90364-6.
Herscher, L L, Krishna, M C, & Cook, J A. Protection against SR 4233 (tirapazamine) aerobic cytotoxicity by the metal chelators desferrioxamine and tiron. United States. doi:10.1016/0360-3016(94)90364-6.
Herscher, L L, Krishna, M C, and Cook, J A. Tue . "Protection against SR 4233 (tirapazamine) aerobic cytotoxicity by the metal chelators desferrioxamine and tiron". United States. doi:10.1016/0360-3016(94)90364-6.
@article{osti_96066,
title = {Protection against SR 4233 (tirapazamine) aerobic cytotoxicity by the metal chelators desferrioxamine and tiron},
author = {Herscher, L L and Krishna, M C and Cook, J A},
abstractNote = {Metal chelating agents and antioxidants were evaluated as potential protectors against aerobic SR 4233 cytotoxicity in Chinese hamster V79 cells. The differential protection of aerobic and hypoxic cells by two metal chelators, desferrrioxamine and Tiron, is discussed in the context of their potential use in the on-going clinical trials with SR 4233. Cytotoxicity was evaluated using clonogenic assay. SR 4233 exposure was done in glass flasks as a function of time either alone or in the presence of the following agents: superoxide dismutase, catalase, 5,5-dimethyl-1-pyrroline, Trolox, ICRF-187, desferrioxamine, Tiron (1,2-dihydroxybenzene-3,5-disulfonate), and ascorbic acid. Experiments done under hypoxic conditions were carried out in specially designed glass flasks that were gassed with humidified nitrogen/carbon dioxide mixture and with a side-arm reservoir from which SR 4233 was added to cell media after hypoxia was obtained. Electron paramagnetic resonance studies were also performed. Electron paramagnetic resonance and spectrophotometry experiments suggest that under aerobic conditions SR 4233 undergoes futile redox cycling to produce superoxide. Treatment of cells during aerobic exposure to SR 4233 with the enzymes superoxide dismutase and catalase, the spin trapping agent DMPO, the water-soluble vitamin E analog Trolox, and the metal chelator ICRF-187 provided little or no protection against aerobic SR 4233 cytotoxicity. However, two other metal chelators, desferrioxamine and Tiron afforded significant protection against minimal protection to hypoxic cells treated with SR 4233. One potential mechanism of aerobic cytotoxicity is redox cycling of SR 4233 with molecular oxygen resulting in several potentially toxic oxidative species that overburden the intrinsic intracellular detoxification systems such as superoxide dismutase, catalase, and glutathione peroxidase. 23 refs., 4 figs., 1 tab.},
doi = {10.1016/0360-3016(94)90364-6},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 4,
volume = 30,
place = {United States},
year = {1994},
month = {11}
}