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.
Papanikolaou
Nikolaos A
NA
Aristotle University of Thessaloniki, School of Medicine, Laboratory of Biological Chemistry, University Campus PO Box 1686, Thessaloniki 54124, Greece. papanikn@med.auth.gr
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