Originally published as JCO Early Release 10.1200/JCO.2005.06.118 on March 7 2005
Journal of Clinical Oncology, Vol 23, No 17 (June 10), 2005: pp. 3897-3905
© 2005 American Society of Clinical Oncology.
Evaluation of a 7-Day Continuous Intravenous Infusion of Decitabine: Inhibition of Promoter-Specific and Global Genomic DNA Methylation
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
From the Huntsman Cancer Institute and the Departments of Internal Medicine (Oncology), Dermatology, Oncological Sciences, and Medicinal Chemistry, University of Utah, Salt Lake City, UT
Address reprint requests to Wolfram E. Samlowski, MD, Huntsman Cancer Institute, Suite 2100 2000 Circle of Hope Dr, Salt Lake City, UT 84112-5550; e-mail: wolfram.samlowski{at}hci.utah.edu.
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 of methylation-silenced genes. It remains unclear to what extent this compound inhibits DNA methylation in vivo. A clinical study was designed to examine the molecular effects and toxicity of a continuous 1-week intravenous infusion of decitabine in solid tumor patients.
METHODS: Ten patients with refractory solid tumors were included in this study. Decitabine was administered at 2 mg/m2/d via continuous infusion for 168 hours. Quantitative polymerase chain reaction and high performance liquid chromatography were utilized to measure promoter-specific and global DNA methylation in peripheral-blood cells before and after treatment.
RESULTS: Transient grade III/IV neutropenia (two patients) and grade II thrombocytopenia (one patient) was observed at the lowest planned dose step (2 mg/m2/d for 7 days). Nonhematologic toxicities were not observed. Quantitative polymerase chain reaction demonstrated significant MAGE-1 promoter hypomethylation by 14 days after the start of treatment in all 13 treatment cycles examined. Significant genomic DNA hypomethylation was also seen by day 14 in 11 of 13 treatment cycles analyzed. Genomic DNA methylation reverted to baseline levels by 28 to 35 days after the start of treatment, demonstrating that inhibition of DNA methylation by decitabine is transient.
CONCLUSION: A 168-hour continuous infusion of decitabine is well tolerated and results in the inhibition of promoter-specific and genomic DNA methylation in vivo. This treatment schedule is suitable for evaluation of decitabine in combination with agents whose activity may be enhanced by the reversal of DNA methylation–mediated gene silencing.
Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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