The design of selective and non-selective combination therapy for acute promyelocytic leukemia.
Acute promyelocytic leukemia (APL) is an unique subtype of acute myeloid leukemia typically carrying a specific reciprocal chromosome translocation, t(15;17), leading to the expression of a leukemia-generating fusion protein, PML-RARalpha. APL patients are responsive to APL-selective reagents such as all-trans retinoic acid (ATRA) or arsenic trioxide and non-selective cytotoxic chemotherapy. Nearly all de novo APL patients undergo clinical remission when treated with ATRA plus chemotherapy or with the combinational selective therapy, ATRA plus As2O3. Combining ATRA with As2O3 as an induction followed by chemotherapy consolidation results in more profound clinical remissions compared to treatment with any agent alone or any of the other possible combinations. The mechanism of action of each of these agents differs. ATRA induces APL cell differentiation and PML-RARalpha proteolysis. As2O3 induces APL cell partial differentiation, PML-RARalpha proteolysis, and apoptosis. Chemotherapy, mainly using anthracyclines, induces APL cell death. The combined effects of selective APL therapy (ATRA and As2O3) and/or non-selective chemotherapy in APL cells in vitro and their mechanisms in relation to clinical protocol design are discussed.
Jing
Y
Y
Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1178, New York, NY 10029-6547, USA.
Waxman
S
S
D018943:Anthracyclines / Q000008:administration & dosage / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D010087:Oxides / Q000008:administration & dosage / Q000627:therapeutic use; D014212:Tretinoin / Q000008:administration & dosage / Q000627:therapeutic use
D018943:Anthracyclines; D000970:Antineoplastic Agents; D001152:Arsenicals; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010087:Oxides; D014212:Tretinoin; D000077237:Arsenic Trioxide