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Differential Cytotoxicity of Diaziquone toward Chinese Hamster Ovary Cells under Hypoxic and Aerobic Exposure Conditions¹

Faculty of Pharmacy, University of Toronto [P. J. O., H. K. K.], and Physics Division, Ontario Cancer Institute [A. M. R.], Toronto, Ontario, Canada M4X 1K9

Diaziquone [AZQ, 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone] has been investigated for its toxicity toward Chinese hamster ovary cells AA8-4 under both aerobic and hypoxic conditions. Under acute (1–5 h) exposures to 2.5–10 µM AZQ in -medium plus 10% fetal calf serum, AZQ showed an approximately linear concentration x time dependency for cell killing which was 3–4 times less under hypoxic compared to aerobic conditions. This selective toxicity toward hypoxic cells was prevented by low levels of oxygen. Under aerobic exposure conditions the toxicity of 2.5 µM AZQ was greatly increased by addition of 1–2 mM ascorbate. This ascorbate mediated toxicity of AZQ, presumably extracellular, could be prevented by the simultaneous addition of catalase. Under hypoxic exposure conditions there was no enhancement of AZQ toxicity by ascorbate or protection by catalase. The present results are consistent with two mechanisms for AZQ toxicity proposed earlier by others: toxicity due to (a) redox cycling and increased levels of oxidative stress and (b) reduction of the quinone leading to enhanced reactivity of the aziridines. The relative potency of AZQ as a hypoxic or aerobic cell selective toxin is determined by the balance between these two mechanisms.

¹ This work was supported by grants from the National Cancer Institute of Canada (H. K. K., P. J. O'B., and A. M. R.), the Medical Research Council (A. M. R.), and the Ontario Cancer Treatment and Research Foundation (A. M. R.).

² To whom requests for reprints should be addressed, at Physics Division, Ontario Cancer Institute, 500 Sherbourne Street, Toronto, Ontario, Canada M4X 1K9.

Received 7/28/89. Revised 11/13/89. Accepted 11/27/89.

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