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Full-Text Articles in Physical Sciences and Mathematics
Inhibition Of Cellular Thioredoxin Reductase By The Anticancer Prodrug Cloretazine, Tyler R. Schleicher
Inhibition Of Cellular Thioredoxin Reductase By The Anticancer Prodrug Cloretazine, Tyler R. Schleicher
Honors Theses
Sulfonylhydrazines are a class of DNA alkylating drugs which also produce carbamoylating activity in situ. The carbamoylating species is of significance because it has shown to inhibit important thiol-containing enzymes such as glutathione reductase (GR) and thioredoxin reductase (TrxR). TrxR catalyzes dithiol-disulfide exchange reactions on thioredoxin (Trx), which in turn catalyzes other reductive processes such as deoxyribonucleotide biosynthesis. In this study, we demonstrate that TrxR activity is strongly inhibited by the anticancer prodrug Cloretazine both in purified form and in leukemia cell lysates. This inhibition is specific to the carbamoylating activity of methylisocyanate (MiC). In contrast, another important oxidoreductase, glutathione …
Effects Of The Anticancer Agent Cloretazine On Human Apurinic Endonuclease-1 Activity, Jennifer L. Bushee
Effects Of The Anticancer Agent Cloretazine On Human Apurinic Endonuclease-1 Activity, Jennifer L. Bushee
Honors Theses
The carbamolyating activity of Cloretazine, a novel anticancer prodrug, modifies protein function and acts synergistically with the choroethyalting species, which a1kylales DNA. The reactive subspecies responsible for carbamolylating activity is methyl isocyanate, which reacts with sulfhydryl groups and amines. DNA repair enzymes have been identified as potential targets for the modification by methyl isocyanate; in particular, base excision repair enzymes. Enzymes in DNA base excision repair include DNA polymerase beta (Pol ?) and apurinic/apyrimidic endonucease-l (APE/Ref-1). APE/Ref-1 hydrolyzes the 5' -phosphodiester DNA backbone from an abasic DNA template, where the base was excised by a DNA glycosylase. The entire nucleotide …