Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia |
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Authors: | Kaufmann Scott H Karp Judith E Litzow Mark R Mesa Ruben A Hogan William Steensma David P Flatten Karen S Loegering David A Schneider Paula A Peterson Kevin L Maurer Matthew J Smith B Douglas Greer Jacqueline Chen Yuhong Reid Joel M Ivy S Percy Ames Matthew M Adjei Alex A Erlichman Charles Karnitz Larry M |
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Affiliation: | Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. kaufmann.scott@mayo.edu |
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Abstract: | BackgroundIn preclinical studies the heat shock protein 90 (Hsp90) inhibitor tanespimycin induced down-regulation of checkpoint kinase 1 (Chk1) and other client proteins as well as increased sensitivity of acute leukemia cells to cytarabine. We report here the results of a phase I and pharmacological study of the cytarabine + tanespimycin combination in adults with recurrent or refractory acute leukemia.Design and MethodsPatients received cytarabine 400 mg/m2/day continuously for 5 days and tanespimycin infusions at escalating doses on days 3 and 6. Marrow mononuclear cells harvested before therapy, immediately prior to tanespimycin, and 24 hours later were examined by immunoblotting for Hsp70 and multiple Hsp90 clients.ResultsTwenty-six patients were treated at five dose levels. The maximum tolerated dose was cytarabine 400 mg/m2/day for 5 days along with tanespimycin 300 mg/m2 on days 3 and 6. Treatment-related adverse events included disseminated intravascular coagulation (grades 3 and 5), acute respiratory distress syndrome (grade 4), and myocardial infarction associated with prolonged exposure to tanespimycin and its active metabolite 17-aminogeldanamycin. Among 21 evaluable patients, there were two complete and four partial remissions. Elevations of Hsp70, a marker used to assess Hsp90 inhibition in other studies, were observed in more than 80% of samples harvested 24 hours after tanespimycin, but down-regulation of Chk1 and other Hsp90 client proteins was modest.ConclusionsBecause exposure to potentially effective concentrations occurs only for a brief time in vivo, at clinically tolerable doses tanespimycin has little effect on resistance-mediating client proteins in relapsed leukemia and exhibits limited activity in combination with cytarabine. |
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Keywords: | cytarabine tanespimycin phase I study pharmacological study acute leukemia |
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