Pharmacological approach for optimization of the dose schedule of 5-Aza-2’-deoxycytidine (Decitabine) for the therapy of leukemia

Abstract

The major mechanisms of resistance to these cytosine nucleoschedule of 5-Aza-CdR should be based on the kinetic paraside analogues are summarized in Table 1. Both 5-Aza-CdR meters of deoxycytidine kinase, its pharmacokinetics, itsand Ara-C must first be phosphorylated by deoxycytidine kin- plastic activity.

Nucleoside analogues: mechanisms of drug resistance and reversal strategies

“…However, these cDNA mutations rarely occur in vivo and therefore may not constitute a major mechanism of clinical NA resistance. 115,116,123 Moreover, it seems that most of the aminoacid replacements did not occur in a functionally relevant region of the enzyme. 124 More recently alternatively spliced forms of dCK mRNA were detected in leukemic blasts from patients with clinically resistant AML but not in leukemic blasts from patients with sensitive AML.…”

Restoration of shp1 expression by 5-AZA-2′-deoxycytidine is associated with downregulation of JAK3/STAT3 signaling in ALK-positive anaplastic large cell lymphoma

“…The aliquoted 5-AZA was frozen at À201C until being used. The final concentrations of 5-AZA used throughout this study were 0, 5 and 10 mM, and the use of these concentrations was based on the findings of two previous studies 34,35 as well as those of our preliminary studies. In all experiments, cells were seeded in six-well culture plates at a density of 10 6 /ml, and 5-AZA in fresh medium was added to the cell culture daily in order to maintain the constant concentration.…”

A hypothesis for the pathogenesis of myelodysplastic syndromes: implications for new therapies

“…100 5-Aza-2Ј-deoxycytidine and 5-azacytidine promote DNA hypomethylation by inhibition of DNA methyltransferase. 101 However, most of the activity of 5-azacytidine, a drug demonstrated to have clinical efficacy, is through mechanisms other than DNA demethylation. 101,102 Incubation of cell lines harboring methylation silenced p 15 with 5-Aza-2Ј-deoxycytidine leads to re-expression of p 15.…”

“…101 However, most of the activity of 5-azacytidine, a drug demonstrated to have clinical efficacy, is through mechanisms other than DNA demethylation. 101,102 Incubation of cell lines harboring methylation silenced p 15 with 5-Aza-2Ј-deoxycytidine leads to re-expression of p 15. 103 In one study, a 72 h infusion of 5-Aza-2Ј-deoxycytidine to 29 high risk MDS patients yielded a 29% complete response rate and 24% partial responses.…”