Oct 22, 2008

Mechanisms of resistance to 5-aza-2'-deoxycytidine in human cancer cell lines

Blood
Taichun QinJean-Pierre J Issa

Abstract

5-aza-2'-deoxycytidine (DAC) is approved for the treatment of myelodysplastic syndromes, but resistance to this agent is common. In search for mechanisms of resistance, we measured the half maximal (50%) inhibitory concentration (IC(50)) of DAC and found it differed 1000-fold among a panel of cancer cell lines. The IC(50) was correlated with the doses of DAC that induced the most hypomethylation of long interspersed nuclear elements (LINE; R = 0.94, P < .001), but not with LINE methylation or DNA methyltransferase 1 (DNMT1), 3a, and 3b expression at baseline. Sensitivity to DAC showed a low correlation (R = 0.44, P = .11) to that of 5-azacytidine (AZA), but a good correlation to that of cytarabine (Ara-C; R = 0.89, P < .001). The 5 cell lines most resistant to DAC had a combination of low dCK, hENT1, and 2 transporters, and high cytosine deaminase. In an HL60 clone, resistance to DAC could be rapidly induced by drug exposure and was related to a switch from heterozygous to homozygous mutation of DCK. Transfection of wild-type DCK restored DAC sensitivity. DAC induced DNA breaks as evidenced by H2AX phosphorylation and increased homologous recombination rates by 7- to 10-fold. These results suggest that in vitro resistance to DA...Continue Reading

Mentioned in this Paper

Cytarabine
H2AFX gene
Transfection
Antibiotic Resistance, Neoplasm
H2AFX wt Allele
Protein Methylation
Antimetabolites, Antineoplastic
Protein Phosphorylation
Decitabine
Inhibitory Concentration 50

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