Aug 13, 1990

The mechanism of action of the nitrosourea anti-tumor drugs on thioredoxin reductase, glutathione reductase and ribonucleotide reductase

Biochimica Et Biophysica Acta
K U SchallreuterJ M Wood

Abstract

The nitrosoureas BCNU, CCNU, ACNU, and Fotemustine covalently deactivate thioredoxin reductase, glutathione reductase and ribonucleotide reductase by alkylating their thiolate active sites. Since thioredoxin reductase and glutathione reductase function as alternative electron donors in the biosynthesis of deoxyribonucleotides, catalyzed by ribonucleotide reductase, the inhibition of these electron transfer systems by the nitrosoureas could determine the cytostatic property of this homologous series of drugs. A detailed study of the kinetics and mechanism for the inhibition of purified thioredoxin reductases from human metastatic melanotic and amelanotic melanomas by the nitrosoureas showed significantly different inhibitor constants. This difference is due to the regulation of these proteins by calcium. Calcium protects thioredoxin reductase from deactivation by the nitrosoureas. In addition, it has been shown that reduced thioredoxin displaces the nitrosourea-inhibitor complex from the active site of thioredoxin reductase to fully reactivate enzyme purified from human metastatic amelanotic melanoma. It has been possible to label the active sites of thioredoxin reductase and glutathione reductase by using chloro[14C]ethyl Fotem...Continue Reading

  • References12
  • Citations56

References

  • References12
  • Citations56

Citations

Mentioned in this Paper

Nitrosoureas, antineoplastic alkylating agents
Enzyme Inhibitor Drugs
Melanoma, Amelanotic
Calcium [EPC]
Thioredoxin Reductase (NADPH)
Antineoplastic Agents
Calcium
Ribonucleotide Reductase
Complex (molecular entity)
Oxidase

About this Paper

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