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

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

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/kg/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.

Original languageEnglish (US)
Pages (from-to)3897-3905
Number of pages9
JournalJournal of Clinical Oncology
Volume23
Issue number17
DOIs
StatePublished - Dec 1 2005

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decitabine
DNA Methylation
Intravenous Infusions
Therapeutics
Polymerase Chain Reaction
Gene Silencing
Neutropenia
Nucleosides
Thrombocytopenia
Methylation
Blood Cells
Neoplasms
Appointments and Schedules

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Evaluation of a 7-day continuous intravenous infusion of decitabine : Inhibition of promoter-specific and global genomic DNA methylation. / Samlowski, Wolfram E.; Leachman, Sancy A.; Wade, Mark; Cassidy, Pamela; Porter-Gill, Patricia; Busby, Leslie; Wheeler, Richard; Boucher, Kenneth; Fitzpatrick, Frank; Jones, David A.; Karpf, Adam R.

In: Journal of Clinical Oncology, Vol. 23, No. 17, 01.12.2005, p. 3897-3905.

Research output: Contribution to journalArticle

Samlowski, WE, Leachman, SA, Wade, M, Cassidy, P, Porter-Gill, P, Busby, L, Wheeler, R, Boucher, K, Fitzpatrick, F, Jones, DA & Karpf, AR 2005, 'Evaluation of a 7-day continuous intravenous infusion of decitabine: Inhibition of promoter-specific and global genomic DNA methylation', Journal of Clinical Oncology, vol. 23, no. 17, pp. 3897-3905. https://doi.org/10.1200/JCO.2005.06.118
Samlowski, Wolfram E. ; Leachman, Sancy A. ; Wade, Mark ; Cassidy, Pamela ; Porter-Gill, Patricia ; Busby, Leslie ; Wheeler, Richard ; Boucher, Kenneth ; Fitzpatrick, Frank ; Jones, David A. ; Karpf, Adam R. / Evaluation of a 7-day continuous intravenous infusion of decitabine : Inhibition of promoter-specific and global genomic DNA methylation. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 17. pp. 3897-3905.
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AU - Cassidy, Pamela

AU - Porter-Gill, Patricia

AU - Busby, Leslie

AU - Wheeler, Richard

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AU - Fitzpatrick, Frank

AU - Jones, David A.

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N2 - 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/kg/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.

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