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

ArticleinPharmacogenomics 13(3):269-82 · February 2012with13 Reads
Impact Factor: 3.22 · DOI: 10.2217/pgs.11.149 · Source: PubMed
Abstract

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.

    • "Of note, ethnicity plays a crucial role in the allelic frequencies of this variant because minor allele frequency (MAF) ranges from 10 % in African population, 15 % in Asian population , but up to 35 % in Caucasians [73, 74]. The phenotypic impact of this allelic variant and its consequence in the clinical outcome in patients treated with nucleoside analogs remain controversial: a decrease in CDA activity has been measured for the Lys 27 Lys variant [75, 76], whereas other studies suggest no variation [52, 77] or lower activity for the Gln 27 Gln variant [78, 79]. These differences may be partly explained by variations in study design such as patient selection, ethnicity and treatment regimens808182. "
    [Show abstract] [Hide abstract] ABSTRACT: Gemcitabine is an antimetabolite ranking among the most prescribed anticancer drugs worldwide. This nucleoside analog exerts its antiproliferative action after tumoral conversion into active triphosphorylated nucleotides interfering with DNA synthesis and targeting ribonucleotide reductase. Gemcitabine is a mainstay for treating pancreatic and lung cancers, alone or in combination with several cytotoxic drugs (nab-paclitaxel, cisplatin and oxaliplatin), and is an option in a variety of other solid or hematological cancers. Several determinants of response have been identified with gemcitabine, i.e., membrane transporters, activating and inactivating enzymes at the tumor level, or Hedgehog signaling pathway. More recent studies have investigated how germinal genetic polymorphisms affecting cytidine deaminase, the enzyme responsible for the liver disposition of gemcitabine, could act as well as a marker for clinical outcome (i.e., toxicity, efficacy) at the bedside. Besides, constant efforts have been made to develop alternative chemical derivatives or encapsulated forms of gemcitabine, as an attempt to improve its metabolism and pharmacokinetics profile. Overall, gemcitabine is a drug paradigmatic for constant searches of the scientific community to improve its administration through the development of personalized medicine in oncology.
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    • "In that study, the response was better in patients with the − 360CG/− 201CT and − 360GG/− 201TT haplotypes [102]. Among the variants identified in the CDA gene, the CDA*2 variant (p.Lys27Gln; c.79A N C) has been associated with higher mortality in children with AML receiving a post-induction regime with ara-C [103], and with cytotoxicity in a subsequent study in adults [104], which also detected a significant association of three variants (c.− 31delC in 5′-UTR, c.816delC in 3′-UTR and TCAT repeat in intron 2) with mRNA levels. In a Swedish study on patients with de novo AML, a significant shorter OS was observed in individuals with the c.79A NC and c.− 451C N T variants of CDA gene, and the outcome was worse in FLT3-ITD-positive patients [105]. "
    [Show abstract] [Hide abstract] ABSTRACT: Acute myeloid leukemia is a clonal but heterogeneous disease differing in molecular pathogenesis, clinical features and response to chemotherapy. This latter frequently consists of a combination of cytarabine and anthracyclines, although etoposide, demethylating agents, and other drugs are also used. Unfortunately, chemoresistance is a common and serious problem. Multiple mechanisms account for impaired effectiveness of drugs and reduced levels of active agents in target cells. The latter can be due to lower drug uptake, increased export or decreased intracellular proportion of active/inactive agent due to changes in the expression/function of enzymes responsible for the activation of pro-drugs and the inactivation of active agents. Characterization of the "resistome", or profile of expressed genes accounting for multi-drug resistance (MDR) phenotype, would permit to predict the lack of response to chemotherapy and would help in the selection of the best pharmacological regime for each patient and moment, and to develop strategies of chemosensitization. Copyright © 2015 Elsevier Ltd. All rights reserved.
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