azacitidine

Overview

Azacitidine (5-azacytidine, Vidaza) is a pyrimidine nucleoside analog hypomethylating agent (HMA) approved for MDS and AML. Like decitabine, it inhibits DNA methyltransferases (DNMT1/3A/3B) but is also incorporated into RNA, giving it dual DNA/RNA targeting activity. It is one of the two standard HMAs used in older/unfit AML patients and MDS; response rates and TP53-predictive relationships are broadly similar to decitabine.

Evidence in the corpus

  • Referenced as a comparator hypomethylating agent in the context of the WashU 10-day decitabine AML/MDS trial (NCT01687400, N=116); the WashU protocol specifically used decitabine (not azacitidine), but azacitidine is discussed as the parallel approved HMA with similar mechanism and the comparator landscape for HMA-based AML/MDS therapy PMID:27959731
  • TP53-mutant AML and MDS are recognized as the population most likely to respond to HMAs including azacitidine, consistent with the 100% blast-clearance rate seen with 10-day decitabine in TP53-mutant patients; azacitidine’s TP53-predictive value is inferred by analogy PMID:27959731
  • 5-Azacitidine (DNA methylation inhibitor) did NOT re-express SLFN11 in SCLC PDX cells, in contrast to EZH2 inhibitor EPZ011989; this implicates histone rather than DNA methylation as the dominant SLFN11 silencing mechanism in SCLC chemoresistance PMID:28196596.
  • 1 KDM5C-frameshift UMD patient derived 6-month stable disease on off-label azacitidine in 860-patient MSK-IMPACT LUAD cohort PMID:28336552.

Resistance mechanisms

  • HMA resistance mechanisms in AML remain incompletely defined; the WashU decitabine trial identified preexisting resistant subclones (not newly acquired mutations) as the dominant relapse mechanism, suggesting clonal architecture rather than acquired mutation drives HMA resistance PMID:27959731

Cancer types (linked)

  • AML — standard HMA option, particularly in TP53-mutant disease.
  • MDS — approved indication; first-line HMA in transfusion-dependent MDS.

Sources

  • PMID:27959731 — Welch et al. 2016, NEJM. WashU 10-day decitabine AML/MDS trial; azacitidine referenced as parallel HMA comparator; TP53-mutant AML as HMA-responsive population.

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