Rational targeting in acute promyelocytic leukemia.
Acute promyelocytic leukemia (ARL) is characterized by the nearly homogeneous expression of the fusion oncogenic protein PML-RARalpha and the testis-specific cyclin A1 protein, which are implicated in its pathogenesis. PML-RARalpha binds all-trans retinoic acid with high affinity inducing granulocytic differentiation and remission. Current approaches with high doses of single or combined all-trans retinoic acid and chemotherapeutic agents, though relatively efficacious in the beginning, are highly toxic with severe side-effects (retinoic acid syndrome) and are followed by relapse in a high proportion of patients. Here it is proposed that targeting APL with low levels of all-trans retinoic acid combined with small molecule inhibitors of cyclin-dependent kinases may have the potential to be equally or more efficacious as any of the current single or combined agent approaches, affording reduced toxicity and relapse rates.
Aristotle University of Thessaloniki, School of Medicine, Laboratory of Biological Chemistry, University Campus PO Box 1686, Thessaloniki 54124, Greece. papanikn@med.auth.gr
Nikolaos A
NA
Papanikolaou
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D014212:Tretinoin; D018844:Cyclin-Dependent Kinases