Differentiation therapy in acute myelogenous leukemia (non-APL).
Successful treatment of acute promyelocytic leukemia (APL) has identified several novel approaches to induce leukemic cell differentiation and selective apoptosis by overcoming the site-specific transcriptional repression by dominant fusion leukemogenic proteins characteristic of APL and other forms of acute myelogenous leukemia (AML). These therapeutic approaches include the use of site-specific ligands, receptors and cytokines, disruption of dominant fusion leukemogenic proteins, chromatin remodeling and combining the above with cytotoxic chemotherapy. With the exception of cytotoxic chemotherapy, the above therapeutic strategies do not significantly affect normal hematopoiesis and their combinations have been shown to be synergistic in inducing myeloid differentiation and apoptosis in several AML cell lines and in patients with APL. These approaches are, in general, non-cross resistant and should be well tolerated particularly in elderly patients with AML. Clinical studies which include biologic end points for differentiation induction, histone acetylation and selective apoptosis are presently in development to evaluate these strategies in the treatment of AML.
Waxman
S
S
Rochelle Belfer Chemotherapy Foundation Laboratory, The Mount Sinai Medical Center, New York, NY, USA.
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects*; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D002843:Chromatin / Q000187:drug effects / Q000648:ultrastructure; D015195:Drug Design; D004357:Drug Synergism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008024:Ligands; D051379:Mice; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics; D010654:Phenylbutyrates / Q000494:pharmacology / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects; D014178:Translocation, Genetic; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D002087:Butyrates; D002843:Chromatin; D008024:Ligands; D015514:Oncogene Proteins, Fusion; D010654:Phenylbutyrates; D016179:Granulocyte Colony-Stimulating Factor; D002762:Cholecalciferol; D014212:Tretinoin; C075773:4-phenylbutyric acid