Christina D Drenberg1,2, Jassada Buaboonnam3, Shelley J Orwick2, Shuiying Hu1,2, Lie Li3, Yiping Fan4, Anang A Shelat5, R Kiplin Guy5, Jeffrey Rubnitz6, Sharyn D Baker7,8. 1. Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 W. 12th St., Columbus, OH, 43210, USA. 2. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. 3. Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA. 4. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. 5. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA. 6. Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA. 7. Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 W. 12th St., Columbus, OH, 43210, USA. baker.2480@osu.edu. 8. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. baker.2480@osu.edu.
Abstract
PURPOSE: Investigate antileukemic activity of artemisinins, artesunate (ART), and dihydroartemisinin (DHA), in combination with cytarabine, a key component of acute myeloid leukemia (AML) chemotherapy using in vitro and in vivo models. METHODS: Using ten human AML cell lines, we conducted a high-throughput screen to identify antimalarial agents with antileukemic activity. We evaluated effects of ART and DHA on cell viability, cytotoxicity, apoptosis, lysosomal integrity, and combination effects with cytarabine in cell lines and primary patient blasts. In vivo pharmacokinetic studies and efficacy of single-agent ART or combination with cytarabine were evaluated in three xenograft models. RESULTS: ART and DHA had the most potent activity in a panel of AML cell lines, with selectivity toward samples harboring MLL rearrangements and FLT3-ITD mutations. Combination of ART or DHA was synergistic with cytarabine. Single-dose ART (120 mg/kg) produced human equivalent exposures, but multiple dose daily administration required for in vivo efficacy was not tolerated. Combination treatment produced initial regression, but did not prolong survival in vivo. CONCLUSIONS: The pharmacology of artemisinins is problematic and should be considered in designing AML treatment strategies with currently available agents. Artemisinins with improved pharmacokinetic properties may offer therapeutic benefit in combination with conventional therapeutic strategies in AML.
PURPOSE: Investigate antileukemic activity of artemisinins, artesunate (ART), and dihydroartemisinin (DHA), in combination with cytarabine, a key component of acute myeloid leukemia (AML) chemotherapy using in vitro and in vivo models. METHODS: Using ten humanAML cell lines, we conducted a high-throughput screen to identify antimalarial agents with antileukemic activity. We evaluated effects of ART and DHA on cell viability, cytotoxicity, apoptosis, lysosomal integrity, and combination effects with cytarabine in cell lines and primary patient blasts. In vivo pharmacokinetic studies and efficacy of single-agent ART or combination with cytarabine were evaluated in three xenograft models. RESULTS:ART and DHA had the most potent activity in a panel of AML cell lines, with selectivity toward samples harboring MLL rearrangements and FLT3-ITD mutations. Combination of ART or DHA was synergistic with cytarabine. Single-dose ART (120 mg/kg) produced human equivalent exposures, but multiple dose daily administration required for in vivo efficacy was not tolerated. Combination treatment produced initial regression, but did not prolong survival in vivo. CONCLUSIONS: The pharmacology of artemisinins is problematic and should be considered in designing AML treatment strategies with currently available agents. Artemisinins with improved pharmacokinetic properties may offer therapeutic benefit in combination with conventional therapeutic strategies in AML.
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