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REVIEW

Changes in DNA Methylation in Neoplasia: Pathophysiology and Therapeutic Implications

right arrow Valeria Santini, MD; Hagop M. Kantarjian, MD; and Jean-Pierre Issa, MD

3 April 2001 | Volume 134 Issue 7 | Pages 573-586

Methylation of DNA is a biochemical modification that can influence gene expression and is involved in inactivating one of the two X chromosomes in women. Evidence that has accumulated in the past 10 years suggests that cancer cells usurp this physiologic mechanism and use it to their benefit by inactivating tumor suppressor genes and related proteins. However, the primary structure of the affected proteins remains intact; reversal of abnormalities in DNA methylation may therefore restore the tumor-suppressive function of these genes and provide a novel approach to cancer therapy. Two demethylating drugs, 5-azacytidine and 5-aza-deoxycytidine, are currently being tested in clinical trials, and several others are in preclinical development. In this article, the biological rationale for targeting aberrant methylation in cancer therapy is reviewed and completed phase I and II trials of this approach, some of which show promise for treatment of hematologic malignancies, are summarized.

Author and Article Information
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From the University of Texas M.D. Anderson Cancer Center, Houston, Texas; and University of Florence, Florence, Italy.

Acknowledgment: The authors thank Maria E. Perez for assistance in preparing the manuscript.

Grant Support: Work in Dr. Issa's laboratory is supported by grants from the National Institutes of Health, The Leukemia and Lymphoma Society of America, and the American Cancer Society.

Requests for Single Reprints: Hagop M. Kantarjian, MD, M.D. Anderson Cancer Center, Leukemia Department, Box 61, 1515 Holcombe Boulevard, Houston, TX 77030.

Current Author Addresses: Dr. Santini: Department of Hematology, University of Florence, Viale Morgagni 85, Florence, Italy.

Drs. Kantarjian and Issa: M.D. Anderson Cancer Center, Leukemia Department, Box 61, 1515 Holcombe Boulevard, Houston, TX 77030.




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