PML-RARalpha inhibitors (ATRA, tamibaroten, arsenic troxide) for acute promyelocytic leukemia.
Acute promyelocytic leukemia (APL) is characterized by generation of the PML-RARalpha fusion gene. PML-RARalpha can homodimerize with another PML-RARalpha, and the hybrid binds the histone-deacetylase recruiting co-repressor complex with higher affinity than the wild-type RARalpha. However, the co-repressor complex is releasable by pharmacological doses of all-trans retinoic acid (ATRA). More than 90% of patients with APL achieve a complete remission (CR) with differentiation therapy consisting of ATRA combined with chemotherapy. A new synthetic retinoid, tamibaroten, showed therapeutic effectiveness in patients with ATRA-resistant APL with increased expression of cellular retinoic acid binding protein (CRABP), and about 60% of patients with relapsed APL achieved a CR. Arsenic trioxide triggers the rapid degradation of PML-RARalpha through the targeting of the PML moieties of the fusion protein and showed a high CR rate in relapsed APL. The combination of ATRA, chemotherapy, and/or new agents improved the long-term survival in patients with APL.
Ohnishi
Kazunori
K
Oncology Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan. kohnishi@hama-med.ac.jp
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D001565:Benzoates / Q000627:therapeutic use*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010087:Oxides / Q000627:therapeutic use*; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use*; D014212:Tretinoin / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001152:Arsenicals; D001565:Benzoates; D015514:Oncogene Proteins, Fusion; D010087:Oxides; D013764:Tetrahydronaphthalenes; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C061133:tamibarotene; D014212:Tretinoin; D000077237:Arsenic Trioxide