title: Synergism between clofarabine and decitabine through p53R2: a pharmacodynamic drug-drug interaction modeling.
abstract: Clofarabine (CLO), a purine nucleoside analog with promising efficacy in acute myeloid leukemia (AML), inhibits the ribonucleotidereductase, p53R2. We have shown that p53R2 mRNA is up-regulated by decitabine (DEC), another drug with promising activity in AML. We developed a pharmacodynamic model to characterize the interaction between CLO and DEC on an AML cell line and down-regulated p53R2 protein to understand its role. These results confirm a role for p53R2 in both CLO and DEC mechanism of action, demonstrate synergism between these two drugs in this AML model and support the use of this combination in a future clinical trial.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Thudium
authors.forename: Sampa
authors.initials: S
authors.lastname: Ghoshal
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Fetterly
authors.forename: Jason P Den
authors.initials: JP
authors.lastname: Haese
authors.forename: Adam R
authors.initials: AR
authors.lastname: Karpf
authors.forename: Meir
authors.initials: M
authors.lastname: Wetzler
mesh_terms: D000227:Adenine Nucleotides / Q000494:pharmacology*; D001087:Arabinonucleosides / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077866:Clofarabine; D000077209:Decitabine; D004357:Drug Synergism; D006801:Humans; D014176:Protein Biosynthesis / Q000187:drug effects; D012264:Ribonucleotide Reductases / Q000378:metabolism*
chemical_list: D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D018797:Cell Cycle Proteins; D000077866:Clofarabine; D000077209:Decitabine; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases; D001374:Azacitidine