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.
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Authors | J I Brodfüehrer, D J Moore, D C Melder, T J Wilke, G Powis |
Journal | Investigational new drugs
(Invest New Drugs)
Vol. 6
Issue 1
Pg. 3-9
(Apr 1988)
ISSN: 0167-6997 [Print] United States |
PMID | 3410664
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antineoplastic Agents
- Pyrazines
- Sulfhydryl Compounds
- pyrazine-2-diazohydroxide
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Topics |
- Animals
- Antineoplastic Agents
(pharmacology)
- Cell Survival
(drug effects)
- Half-Life
- Humans
- Hydrogen-Ion Concentration
- Male
- Microsomes, Liver
(drug effects, metabolism)
- Pyrazines
(pharmacology)
- Rats
- Rats, Inbred F344
- Rhabdomyosarcoma
(pathology)
- Sulfhydryl Compounds
(metabolism)
- Tumor Cells, Cultured
(drug effects, pathology)
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