title: In vitro cytotoxicity of pyrazine-2-diazohydroxide: specificity for hypoxic cells and effects of microsomal coincubation.
abstract: 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 micrograms/ml and at pH of 6.0 it was 31 micrograms/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 micrograms/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.
authors.affiliation: Department of Pharmacology, Mayo Clinic & Foundation, Rochester, MN 55905.
authors.forename: J I
authors.initials: JI
authors.lastname: Brodfüehrer
authors.forename: D J
authors.initials: DJ
authors.lastname: Moore
authors.forename: D C
authors.initials: DC
authors.lastname: Melder
authors.forename: T J
authors.initials: TJ
authors.lastname: Wilke
authors.forename: G
authors.initials: G
authors.lastname: Powis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects*; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D012208:Rhabdomyosarcoma / Q000473:pathology; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D011719:Pyrazines; D013438:Sulfhydryl Compounds; C051397:pyrazine-2-diazohydroxide