Cytidine deaminase genetic variants influence RNA expression and cytarabine cytotoxicity in acute myeloid leukemia

Christian Medical College, Vellore 632004, India.
Pharmacogenomics (Impact Factor: 3.22). 02/2012; 13(3):269-82. DOI: 10.2217/pgs.11.149
Source: PubMed


Cytidine deaminase (CDA) irreversibly deaminates cytarabine (Ara-C), a key component of acute myeloid leukemia (AML) induction and consolidation therapy. CDA overexpression results in Ara-C resistance, while decreased expression is associated with toxicity. We evaluated factors influencing variation in CDA mRNA expression in adult AML patients and normal controls, and how they contributed to Ara-C cytotoxicity in AML cells.
CDA mRNA expression in 100 de novo AML patients and 36 normal controls were determined using quantitative reverse-transcriptase PCR. Genetic variants in the CDA gene were screened by direct sequencing. IC₅₀ of Ara-C was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.
CDA RNA expression as well as Ara-C IC₅₀ showed wide variation in AML samples and normal controls. Fourteen sequence variants were identified, three of which (-33delC, intron 2 TCAT repeat and the 3´untranslated region 816delC variants) showed significant association with RNA expression and the nonsynonymous coding variant 79A>C was associated with Ara-C cytotoxicity.
CDA genetic variants explain the variation in RNA expression and may be candidates for individualizing Ara-C therapy.

12 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cytosine arabinoside (cytarabine or Ara-C) has been one of the cornerstones of treatment of acute myeloid leukemia since its approval in 1969. Standard induction therapy worldwide for all patients deemed fit for treatment (excluding those with acute promyelocytic leukemia) remains unchanged for over 40 years and consists of Ara-C administered by continuous infusion in combination with a topoisomerase II inhibitor (e.g., daunorubicin, idarubicin and mitoxantrone). Despite decades of clinical investigation, the optimum dose of both agents still remains unclear. Although higher doses of Ara-C have been shown to improve response rates, the elderly poorly tolerate these regimens. Resistance mechanisms also develop or may be present at diagnosis resulting in poor outcomes. Elacytarabine (CP-4055), an elaidic acid ester of Ara-C, has been developed using lipid vector technology in an attempt to overcome these limitations. Clinical data are encouraging, with evidence suggesting that this novel agent is circumventing resistance mechanisms but retaining the potent antileukemic efficacy of Ara-C.
    Expert Review of Hematology 02/2013; 6(1):9-24. DOI:10.1586/ehm.12.68 · 2.07 Impact Factor
  • Pharmacogenomics 02/2013; 14(3):227-30. DOI:10.2217/pgs.12.208 · 3.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The elucidation of drug resistance mechanisms is very important in the development of clinical therapies for the treatment of leukemia. To study the drug resistance mechanisms, protein expression profiles of 1-β-D-arabinofuranosylcytosine (AraC) sensitive K562 (K562S) cells and AraC resistant K562 (K562AC) cells were compared using two-dimensional fluorescence difference gel electrophoresis. In comparison of protein expression profiles, 2073 protein spots were found to be altered, 15 proteins of them were remarkably altered. These proteins were identified by mass spectrometry. The most differently expressed proteins were aldehyde dehydrogenase 1 family member A2 (ALDH1A2) and vimentin. Both proteins were verified using reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot analysis. ALDH1A2 protein was found to be effective in AraC resistance. ALDH1A2 knock down (KD) induced sensitivity to AraC treatment in K562AC cells, and ALDH1A2 overexpressed K562S cells acquired the AraC resistance. Further, the findings also suggest that ALDH1A2 expression is increased after the appearance of AraC resistance in clinical cases. These results will be helpful in understanding the mechanism of AraC resistance.
    Experimental hematology 03/2013; 41(7). DOI:10.1016/j.exphem.2013.03.004 · 2.48 Impact Factor
Show more