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Decitabine--bedside to bench
Yasuhiro Oki1, Etsuko Aoki, Jean-Pierre J Issa
1Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. yooki-tky@umin.ac.jp
Purpose Of The Review:
Epigenetic changes marked by DNA methylation are known to contribute to the malignant transformation of cells by silencing critical genes. Decitabine inhibits DNA methyltransferase and has shown therapeutic effects in patients with hematologic malignancies. However, the connection between the clinical activity of decitabine and its demethylating activity is not clear. Herein, we summarize the results of recent clinical trials of decitabine in hematologic malignancies, and review the translational research into decitabine's mechanism of clinical activity.
Recent Findings:
Low-dose decitabine has been studied recently in multiple clinical trials and has been shown to be effective for treatment of myelodysplastic syndromes. Correlative laboratory studies of clinical trials have shown that decitabine induces global hypomethylation as well as hypomethylation of gene-specific promoters and activation of gene expression. Past a given threshold, induction of higher degrees of hypomethylation is not directly associated with a better clinical outcome. Moreover, studies have suggested that patients with promoter hypermethylation of p15(INK4B) at baseline have paradoxically a lower chance of achieving response than those without hypermethylation. Furthermore, several other genes activated by decitabine were independent of hypomethylation in the promoter regions.
Conclusion:
While at least part of decitabine's activity is through induction of hypomethylation and reactivation of critical genes, mechanisms independent from hypomethylation are also important for decitabine's antitumor activity.
Insights
Decitabine shows therapeutic effects in hematologic malignancies by demethylating DNA and reactivating genes. However, its clinical activity is not solely dependent on DNA hypomethylation, suggesting alternative mechanisms are also at play.
Area of Science:
- Oncology
- Epigenetics
- Pharmacology
Background:
- DNA methylation is crucial in cell malignant transformation by silencing genes.
- Decitabine, a DNA methyltransferase inhibitor, demonstrates therapeutic potential in hematologic malignancies.
- The precise link between decitabine's clinical efficacy and its DNA demethylating activity requires further elucidation.
Purpose of the Study:
- To review recent clinical trials of decitabine in hematologic malignancies.
- To explore the translational research investigating decitabine's mechanism of clinical activity.
Main Methods:
- Review of recent clinical trials involving decitabine.
- Analysis of correlative laboratory studies from clinical trials.
- Examination of translational research on decitabine's mechanisms.
Main Results:
- Low-dose decitabine is effective in myelodysplastic syndromes, inducing global and gene-specific hypomethylation.
- Clinical response is not directly correlated with the degree of hypomethylation beyond a certain threshold.
- Baseline p15(INK4B) hypermethylation paradoxically correlates with a lower response rate.
- Decitabine activates several genes independently of promoter hypomethylation.
Conclusions:
- Decitabine's antitumor activity involves DNA hypomethylation and gene reactivation.
- Mechanisms independent of DNA hypomethylation significantly contribute to decitabine's efficacy.
