Treatment of acute promyelocytic leukemia with arsenic trioxide: clinical and basic studies.
Arsenic trioxide (As2O3) has recently been identified as an effective drug in the treatment of newly diagnosed and relapsed acute promyelocytic leukemia (APL) without cross-resistance to all-trans retinoic acid and achieved complete remission rates of 80-90% according to most reports. With intravenous infusion at a dose of 0.08-0.16 mg/kg daily, a course of 28-42 days is required to induce remission. As2O3 in combination with chemotherapy as postremission therapy results in longer survival than arsenic alone. In vitro, As2O3 exerts dose-dependent dual effect; triggering apoptosis at relatively high concentration (0.5-2.0 micromol/l), which is associated with the disruption of mitochondrial transmembrane potentials, while inducing partial differentiation at low concentration (0.1-0.5 micromol/l), which might be related to retinoic acid signaling pathway. Importantly, at both concentrations, As2O3 can degrade PML (promyelocytic leukemia) -RAR alpha (retinoic acid receptor), an oncoprotein that has a central role in leukemogenesis.
Zhao
W L
WL
Shanghai Institute of Hematology, Rui Jin Hospital affiliated to Shanghai Second Medical University, People's Republic of China.
Chen
S J
SJ
Shen
Y
Y
Xu
L
L
Cai
X
X
Chen
G Q
GQ
Shen
Z X
ZX
Chen
Z
Z
Wang
Z Y
ZY
D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010087:Oxides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism
D001152:Arsenicals; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D010087:Oxides; D011993:Recombinant Fusion Proteins; D013438:Sulfhydryl Compounds; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D000077237:Arsenic Trioxide