Date of Award


Document Type

Honors Thesis (Open Access)


Colby College. Chemistry Dept.


Kevin P. Rice

Second Advisor

Julie Millard

Third Advisor

Jeffrey Katz


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 is then re-inserted by the nucleotidyl transferase activity of Pol ?, which also cleaves the 5' -deoxyribose phosphate via lyase activity. Previous research in our laboratory investigated the inhibition of Pol ?'s AP lyase and nucleoside transferase activity. Cloretazine's carbamoylating activity inhibits the nucleotidyl transferase activity of Pol-?, but not its lyase activity. An efficient enzymatic assay was developed and used to determine the anticancer drug's effect on APE/Ref-1's hydrolytic activity. We found that the endonucleolytic activity of APE-1 is not significantly inhibited by Cloretazine.


Cloretazine, Antineoplastic agents, DNA repair

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