Novel therapies for myelodysplastic syndromes.
Preliminary therapeutic successes have prompted a new wave of clinical trials enrolling patients with myelodysplastic syndromes (MDS), using compounds with a broad range of potential mechanisms of action. This article discusses several of the agents currently in development for MDS, reviewing clinical trial data related to five classes of novel therapeutics: clofarabine, a halogenated purine nucleoside analog; ezatiostat (TLK199), a glutathione analog that indirectly activates c-Jun kinase; tipifarnib, a farnesyltransferase inhibitor; laromustine (cloretazine), an alkylating agent with a metabolite that inhibits one mechanism of DNA damage repair; and eight drugs that inhibit histone deacetylase. Although MDS are still difficult clinical problems, and most patients with MDS still succumb to disease-related complications within 3 to 5 years of diagnosis, ongoing development of novel agents promises that there will be new treatment options for patients within the next 5 to 10 years.
Steensma
David P
DP
Department of Hematologic Malignancies, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. david_steensma@dfci.harvard.edu
D000227:Adenine Nucleotides / Q000494:pharmacology / Q000627:therapeutic use; D000368:Aged; D000477:Alkylating Agents / Q000494:pharmacology / Q000627:therapeutic use; D000963:Antimetabolites / Q000494:pharmacology; D001087:Arabinonucleosides / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D000077866:Clofarabine; D004260:DNA Repair / Q000187:drug effects; D004359:Drug Therapy, Combination; D015507:Drugs, Investigational / Q000627:therapeutic use*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology / Q000627:therapeutic use; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D035703:Therapies, Investigational
D000227:Adenine Nucleotides; D000477:Alkylating Agents; D000963:Antimetabolites; D001087:Arabinonucleosides; D015507:Drugs, Investigational; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006834:Hydrazines; D015363:Quinolones; D013449:Sulfonamides; C096329:gamma-Glu-S-BzCys-PhGly diethyl ester; C483604:laromustine; D000077866:Clofarabine; D051231:Farnesyltranstransferase; D048031:JNK Mitogen-Activated Protein Kinases; D005978:Glutathione; C402769:tipifarnib