Abstract:
AIM: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. MATERIALS & METHODS: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. RESULTS: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. CONCLUSION:CDA genetic variants explain the variation in RNA expression and may be candidates for individualizing Ara-C therapy.
journal_name
Pharmacogenomicsjournal_title
Pharmacogenomicsauthors
Abraham A,Varatharajan S,Abbas S,Zhang W,Shaji RV,Ahmed R,Abraham A,George B,Srivastava A,Chandy M,Mathews V,Balasubramanian Pdoi
10.2217/pgs.11.149subject
Has Abstractpub_date
2012-02-01 00:00:00pages
269-82issue
3eissn
1462-2416issn
1744-8042journal_volume
13pub_type
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