Arsenic compounds, Including
arsenic trioxide (
As2O3) and
arsenic sulfide (As4S4), have recently been shown to be effective in the treatment of
acute promyelocytic leukemia (APL). In vitro,
As2O3 exerts a dose-dependent dual effect: it triggers apoptosis at relatively high concentrations (0.5 to 2.0 micromol/L) and induces partial differentiation at low concentrations (0.1 to 0.5 micromol/L). The apoptosis-inducing effect is associated with the collapse of mitochondrial transmembrane potentials in a
thiol-dependent manner, whereas the
retinoic acid signaling is required for APL cell differentiation.
As2O3 over a wide range of concentrations (0.1 to 2.0 micromol/L) Induces degradation of
PML-RARalpha as well as the wild-type PML and enhances the acetylation of
histone, a process important for the transcriptional activation of genes. In vivo,
As2O3 induces a high complete remission (CR) rate in patients with both primary and relapsed APL (around 85% to 90%). Side effects, such as skin reaction, gastrointestinal symptoms, electrocardiographic (EKG) changes, neuropathy, and
liver dysfunction, are mild to moderate in relapsed patients, and severe hepatic lesions have been found in some primary cases. After CR obtained in relapsed patients,
chemotherapy in combination with
As2O3 as postremission
therapy has yielded better survival than treatment with
As2O3 alone. This is in line with the observation that
remission induction with
As2O3 is not sufficient in most cases to obtain a molecular remission as Judged by
reverse-transcriptase polymerase chain reaction for
PML-RARalpha fusion transcripts. The in vivo effect of
As2O3 seems to be related to the expression of APL-specific
PML-RARalpha oncoprotein, and a synergistic effect between
As2O3 and ATRA has been shown in the APL mouse model. Besides
As2O3, other
arsenic compounds such as As4S4 also show a
therapeutic effect in APL. Because the toxic effects of
arsenic treatment in primary APL need to be investigated further, we propose use of ATRA as a first-line
drug for
remission induction in primary APL, whereas
As2O3 can be incorporated into multidrug postremission
therapy or used as rescue for relapsed APL patients.