Evaluation of a 7-Day Continuous Intravenous Infusion of Decitabine: Inhibition of Promoter-Specific and Global Genomic DNA Methylation

• DOI: 10.1200/jco.2005.06.118
• Publication Date: 2005-03-08T01:43:22Z
• Authors: Wolfram E. Samlowski; Sancy A. Leachman; Mark Wade; Pamela Cassidy; Patricia Porter-Gill; Leslie Busby; Richard Wheeler; Kenneth Boucher; Frank Fitzpatrick; David A. Jones; Adam R. Karpf
• Keywords: Decitabine; genomic DNA

Purpose The nucleoside analog 5-aza-2′-deoxycytidine (5-aza-CdR, decitabine) is a potent inhibitor of DNA methylation in vitro. Cellular treatment with this agent induces the re-expression methylation-silenced genes. It remains unclear to what extent compound inhibits vivo. A clinical study was designed examine molecular effects and toxicity continuous 1-week intravenous infusion decitabine solid tumor patients. Methods Ten patients refractory tumors were included study. Decitabine administered at 2 mg/m /d via for 168 hours. Quantitative polymerase chain reaction high performance liquid chromatography utilized measure promoter-specific global peripheral-blood cells before after treatment. Results Transient grade III/IV neutropenia (two patients) II thrombocytopenia (one patient) observed lowest planned dose step (2 7 days). Nonhematologic toxicities not observed. demonstrated significant MAGE-1 promoter hypomethylation by 14 days start all 13 cycles examined. Significant genomic also seen day 11 analyzed. Genomic reverted baseline levels 28 35 treatment, demonstrating that inhibition transient. Conclusion 168-hour well tolerated results This schedule suitable evaluation combination agents whose activity may be enhanced reversal methylation–mediated gene silencing.