TY - JOUR
T1 - Decitabine-Bedside to bench
AU - Oki, Yasuhiro
AU - Aoki, Etsuko
AU - Issa, Jean Pierre J.
N1 - Funding Information:
Dr. Allen Yang, USC/Norris Cancer Center, 1441 Eastlake Ave, MC-9172 University of Southern California, Los Angeles, CA 90089, United States. E-mail: allenyan@usc.edu . Dr. Steven D. Gore, Johns Hopkins University, Department of Oncology, 1650 Orleans Street, Baltimore, MD 21231, United States. E-mail: steven.gore@jhu.edu . Yasuhiro Oki , M.D., is a medical oncology fellow at The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Ongoing research topics include epigenetic analyses and epigenetic therapy in myelodysplastic syndrome. He is a recipient of an American Society of Clinical Oncology Young Investigator Award 2005–2006. Etsuko Aoki , M.D., Ph.D., is a leukemia fellow at The University of Texas M.D. Anderson Cancer Center. She obtained her Ph.D. in molecular biology, mostly focusing on epigenetic analyses in myelodysplastic syndrome. She currently is involved in clinical research on prognostic factors in chronic myelogenous leukemia. Jean-Pierre J. Issa , M.D., is professor of medicine at The University of Texas M.D. Anderson Cancer Center. He directs clinical trials on epigenetic therapy and runs a laboratory focusing on cancer biology, particularly epigenetic analyses.
PY - 2007/2
Y1 - 2007/2
N2 - 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 p15INK4B 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.
AB - 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 p15INK4B 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.
KW - DNA methylation
KW - DNA methyltransferase
KW - Decitabine
KW - Hematologic malignancies
KW - Leukemia
KW - Myelodysplastic syndrome
KW - Translational research
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U2 - 10.1016/j.critrevonc.2006.07.010
DO - 10.1016/j.critrevonc.2006.07.010
M3 - Review article
C2 - 17023173
AN - SCOPUS:33846117560
SN - 1040-8428
VL - 61
SP - 140
EP - 152
JO - Critical Reviews in Oncology/Hematology
JF - Critical Reviews in Oncology/Hematology
IS - 2
ER -