Epigenetic treatment of hematopoietic malignancies: in vivo targets of demethylating agents.
Although the first studies using DNA demethylating agents at low doses in hematologic neoplasia and hemoglobinopathies were initiated more than 20 years ago, development of this type of nonintensive treatment has only been spurred in the last 6 to 8 years by the discovery of many genes that are specifically hypermethylated in cancer. These provide a powerful rationale for using azanucleosides (and other small molecules being developed for DNA demethylation) as a novel means of pharmacologic targeting of cancer cells that is distinct from low-dose chemotherapy. Encouraging response rates of about 50% in myelodysplasia with 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine or DAC) have resulted in a number of phase III studies being initiated in this disorder. The development of such drugs for the treatment of acute myeloid leukemia (AML) is ongoing. While the specificity of DNA demethylation has been delineated by studying distinct genes or sets of genes, and proof-of-principle studies of in vivo methylation report demethylation and reactivation of genes like p15/INK4b and gamma-globin, responses to demethylating agents may be more complex. Specifically, so-called cancer testis antigens (CTAs) are intriguing targets for demethylation, since they are silenced in many hematopoietic disorders and may be reactivated by epigenetic therapy. Thus, demethylating agents and histone deacetylase inhibitors may also induce a T-cell-mediated antileukemic or antitumor effect.
Claus
Rainer
R
Department Internal Medicine I, Division Hematology/Oncology, University of Freiburg Medical Center, Hugstetterstrasse 55, D-79106 Freiburg, Germany. Claus@mm11.ukl.uni-freiburg.de
Almstedt
Maika
M
Lübbert
Michael
M
D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000737:chemistry; D018797:Cell Cycle Proteins / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15; D004247:DNA / Q000737:chemistry; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000627:therapeutic use*; D000077209:Decitabine; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008565:Membrane Proteins / Q000378:metabolism; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C493966:CDKN2B protein, human; C104948:CTAG1B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; D000077209:Decitabine; D004247:DNA; D015254:DNA Modification Methylases; D001374:Azacitidine