Summary
The antitumor drug pyrazine-2-diazohydroxide exhibits cytotoxicity to A204 tumor cells in vitro under acid conditions. The IC50 with a 1 hr drug exposure at pH of 7.4 was 61 μg/ml and at pH of 6.0 it was 31 μg/ml. It is suggested that the increased cytotoxicity is due to the acid catalyzed formation of a reactive pyrizinyldiazonium ion from pyrazine-2-diazohydroxide. Pyrazine-2-diazohydroxide is also more cytotoxic to A204 cells under hypoxic conditions in the presence of glucose with an IC50 at pH 7.4 of 22 μg/ml. The increased cytotoxicity of pyrazine-2-diazohydroxide under acid and hypoxic conditions may favor selective toxicity to solid tumors in vivo. Coincubation with rat hepatic microsomes increased the cytotoxicity of pyrazine-2-diazohydroxide to A204 cells. The effect did not require NADPH and was not due to formation of metabolites. There was an increased rate of degradation of pyrazine-2-diazohydroxide in the presence of microsomes, presumably with formation of the pyrizinyldiazonium ion. The final degradation product 2-hydroxypyrazine was not cytotoxic to A204 cells. The effect of microsomes on pyrazine-2-diazohydroxide cytotoxicity is probably of little in vivo significance.
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Brodfüehrer, J.I., Moore, D.J., Melder, D.C. et al. In vitro cytotoxicity of pyrazine-2-diazohydroxide: specificity for hypoxic cells and effects of microsomal coincubation. Invest New Drugs 6, 3–9 (1988). https://doi.org/10.1007/BF00170773
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DOI: https://doi.org/10.1007/BF00170773