tretinoin and arsenic-trichloride

After being in the therapeutic wilderness for several decades, acute myeloid leukemia has been recently thrust into the limelight with a series of drug approvals. Technical refinements in production, genetic manipulation and chemical modification of monoclonal antibodies led to growing interest in antibodies-based treatment strategies. Much of the focus of these efforts in acute myeloid leukemia has been on CD33 as a target. On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin for treatment of relapsed or refractory CD33

Topics: Aged; Animals; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Calicheamicins; Chlorides; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Approval; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Gemtuzumab; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Mice; Middle Aged; Multicenter Studies as Topic; Recurrence; Sialic Acid Binding Ig-like Lectin 3; Tretinoin

Treatment of APL with ATRA or As2O3 alone or in combination with chemotherapy yields a complete remission as high as 85%-95%, but their mechanisms of action remain unclear. The mechanisms of action underlying ATRA treatment are (1) relocalization of the PML restoration of normal structure of nuclear bodies and degradation of PML-RAR alpha protein via caspase-mediated cleavage and proteosome-dependent degradation; (2) conversion of PML-RAR alpha from a transcription repressor (CoR) to a transcription activator (CoA) under therapeutic concentration of ATRA (3) coordinated genes expression induced by ATRA resulting in an elegant and intricate cellular program for the commitment to differentiation. 169 genes were modulated to express, with 100 genes up-regulated and 69 down-regulated. As2O3 exerts its action by dual dose-dependent manner. At higher concentration (1-2 microns/l), it induces apoptosis of the leukemic cells associated with disruption of mitochondrial membrane potential, elevation of caspase-3 and other caspases activity and decline of Bcl-2 expression. At lower concentration (0.1-0.5 micron/l), it triggers differentiation with elevation of CD11b expression accompanied by morphologically partial differentiation. At both concentrations, As2O3 causes degradation of PML-RAR alpha protein implicated probably in its mechanisms of action.

Topics: Antineoplastic Agents; Apoptosis; Arsenicals; Cell Differentiation; Chlorides; Humans; Leukemia, Promyelocytic, Acute; Tretinoin