Protection against sr 4233 (tirapazamine) aerobic cytotoxicity by the metal chelators desferrioxamine and tiron

Laurie L. Herscher, Murali C. Krishna, John A. Cook, C. Norman Coleman, John E. Biaglow, Stephen W. Tuttle, Frank J. Gonzalez, James B. Mitchell

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: 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. Methods and Materials: 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-l-pyrioline, 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. Results: 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 aerobic SR 4233 cytotoxicity (protection factors at 50% survival were 3.8 and 3.1, respectively), while exhibiting minimal protection to hypoxic cells treated with SR 4233. Conclusions: 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. This study identifies two metal chelating agents, desferrioxarnine and Tiron, that were able to protect against aerobic but not hypoxic SR 4233 cytotoxicity.

Original languageEnglish (US)
Pages (from-to)879-885
Number of pages7
JournalInternational journal of radiation oncology, biology, physics
Volume30
Issue number4
DOIs
StatePublished - Nov 15 1994

Keywords

  • Aerobic cytotoxicity
  • Desferrioxamine
  • SR 4233
  • Tiron

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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