Increased CDA Expression/Activity in Males Contributes to Decreased Cytidine Analog Half-Life and Likely Contributes to Worse Outcomes with 5-Azacytidine or Decitabine Therapy
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- Reda Z. Mahfouz
- Authors' Affiliations: 1Department of Translational Hematology & Oncology Research and 2Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; 4NCTT, Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences; 5Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and diagnosis, NCI, NIH, Bethesda, Maryland; 6College of Pharmacy, The Ohio State University, Columbus, Ohio; and 7AVANZA Laboratories, Gaithersburg, Maryland
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- Ania Jankowska
- Authors' Affiliations: 1Department of Translational Hematology & Oncology Research and 2Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; 4NCTT, Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences; 5Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and diagnosis, NCI, NIH, Bethesda, Maryland; 6College of Pharmacy, The Ohio State University, Columbus, Ohio; and 7AVANZA Laboratories, Gaithersburg, Maryland
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- Quteba Ebrahem
- Authors' Affiliations: 1Department of Translational Hematology & Oncology Research and 2Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; 4NCTT, Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences; 5Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and diagnosis, NCI, NIH, Bethesda, Maryland; 6College of Pharmacy, The Ohio State University, Columbus, Ohio; and 7AVANZA Laboratories, Gaithersburg, Maryland
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- Xiaorong Gu
- Authors' Affiliations: 1Department of Translational Hematology & Oncology Research and 2Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; 4NCTT, Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences; 5Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and diagnosis, NCI, NIH, Bethesda, Maryland; 6College of Pharmacy, The Ohio State University, Columbus, Ohio; and 7AVANZA Laboratories, Gaithersburg, Maryland
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- Valeria Visconte
- Authors' Affiliations: 1Department of Translational Hematology & Oncology Research and 2Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; 4NCTT, Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences; 5Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and diagnosis, NCI, NIH, Bethesda, Maryland; 6College of Pharmacy, The Ohio State University, Columbus, Ohio; and 7AVANZA Laboratories, Gaithersburg, Maryland
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- Ali Tabarroki
- Authors' Affiliations: 1Department of Translational Hematology & Oncology Research and 2Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; 4NCTT, Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences; 5Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and diagnosis, NCI, NIH, Bethesda, Maryland; 6College of Pharmacy, The Ohio State University, Columbus, Ohio; and 7AVANZA Laboratories, Gaithersburg, Maryland
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- Pramod Terse
- Authors' Affiliations: 1Department of Translational Hematology & Oncology Research and 2Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; 4NCTT, Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences; 5Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and diagnosis, NCI, NIH, Bethesda, Maryland; 6College of Pharmacy, The Ohio State University, Columbus, Ohio; and 7AVANZA Laboratories, Gaithersburg, Maryland
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- Joseph Covey
- Authors' Affiliations: 1Department of Translational Hematology & Oncology Research and 2Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; 4NCTT, Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences; 5Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and diagnosis, NCI, NIH, Bethesda, Maryland; 6College of Pharmacy, The Ohio State University, Columbus, Ohio; and 7AVANZA Laboratories, Gaithersburg, Maryland
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- Kenneth Chan
- Authors' Affiliations: 1Department of Translational Hematology & Oncology Research and 2Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; 4NCTT, Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences; 5Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and diagnosis, NCI, NIH, Bethesda, Maryland; 6College of Pharmacy, The Ohio State University, Columbus, Ohio; and 7AVANZA Laboratories, Gaithersburg, Maryland
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- Yonghua Ling
- Authors' Affiliations: 1Department of Translational Hematology & Oncology Research and 2Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; 4NCTT, Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences; 5Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and diagnosis, NCI, NIH, Bethesda, Maryland; 6College of Pharmacy, The Ohio State University, Columbus, Ohio; and 7AVANZA Laboratories, Gaithersburg, Maryland
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- Kory J. Engelke
- Authors' Affiliations: 1Department of Translational Hematology & Oncology Research and 2Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; 4NCTT, Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences; 5Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and diagnosis, NCI, NIH, Bethesda, Maryland; 6College of Pharmacy, The Ohio State University, Columbus, Ohio; and 7AVANZA Laboratories, Gaithersburg, Maryland
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- Mikkael A. Sekeres
- Authors' Affiliations: 1Department of Translational Hematology & Oncology Research and 2Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; 4NCTT, Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences; 5Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and diagnosis, NCI, NIH, Bethesda, Maryland; 6College of Pharmacy, The Ohio State University, Columbus, Ohio; and 7AVANZA Laboratories, Gaithersburg, Maryland
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- Ramon Tiu
- Authors' Affiliations: 1Department of Translational Hematology & Oncology Research and 2Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; 4NCTT, Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences; 5Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and diagnosis, NCI, NIH, Bethesda, Maryland; 6College of Pharmacy, The Ohio State University, Columbus, Ohio; and 7AVANZA Laboratories, Gaithersburg, Maryland
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- Jaroslaw Maciejewski
- Authors' Affiliations: 1Department of Translational Hematology & Oncology Research and 2Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; 4NCTT, Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences; 5Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and diagnosis, NCI, NIH, Bethesda, Maryland; 6College of Pharmacy, The Ohio State University, Columbus, Ohio; and 7AVANZA Laboratories, Gaithersburg, Maryland
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- Tomas Radivoyevitch
- Authors' Affiliations: 1Department of Translational Hematology & Oncology Research and 2Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; 4NCTT, Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences; 5Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and diagnosis, NCI, NIH, Bethesda, Maryland; 6College of Pharmacy, The Ohio State University, Columbus, Ohio; and 7AVANZA Laboratories, Gaithersburg, Maryland
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- Yogen Saunthararajah
- Authors' Affiliations: 1Department of Translational Hematology & Oncology Research and 2Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic; 3Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio; 4NCTT, Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences; 5Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and diagnosis, NCI, NIH, Bethesda, Maryland; 6College of Pharmacy, The Ohio State University, Columbus, Ohio; and 7AVANZA Laboratories, Gaithersburg, Maryland
説明
<jats:title>Abstract</jats:title> <jats:p>Purpose: The cytidine analogs 5-azacytidine and decitabine, used to treat myelodysplastic syndromes (MDS), produce a molecular epigenetic effect, depletion of DNA-methyltransferase 1 (DNMT1). This action is S-phase dependent. Hence, genetic factors that decrease the half-lives of these drugs could impact efficacy. Documentation of such impact, and elucidation of underlying mechanisms, could lead to improved clinical application.</jats:p> <jats:p>Experimental design: Cytidine deaminase (CDA) rapidly inactivates 5-azacytidine/decitabine. The effect of CDA SNP A79C and gender on CDA expression, enzyme activity, and drug pharmacokinetics/pharmacodynamics was examined in mice and humans, and the impact on overall survival (OS) was evaluated in 5-azacytidine/decitabine-treated patients with MDS (n = 90) and cytarabine-treated patients with acute myeloid leukemia (AML) (n = 76).</jats:p> <jats:p>Results: By high-performance liquid chromatography (HPLC), plasma CDA activity was decreased as expected in individuals with the SNP A79C. Interestingly and significantly, there was an even larger decrease in females than in males. Explaining this decrease, liver CDA expression was significantly lower in female versus male mice. As expected, decitabine plasma levels, measured by mass spectrometry, were significantly higher in females. In mathematical modeling, the detrimental impact of shorter drug half-life (e.g., in males) was greater in low compared with high S-phase fraction disease (e.g., MDS vs. AML), because in high S-phase fraction disease, even a short exposure treats a major portion of cells. Accordingly, in multivariate analysis, OS was significantly worse in male versus female patients with MDS treated with 5-azacytidine/decitabine.</jats:p> <jats:p>Conclusions: Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy. Clin Cancer Res; 19(4); 938–48. ©2012 AACR.</jats:p>
収録刊行物
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- Clinical Cancer Research
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Clinical Cancer Research 19 (4), 938-948, 2013-02-14
American Association for Cancer Research (AACR)