Treatment of acute promyelocytic leukemia with arsenic compounds: In vitro and in vivo studies

Abstract

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.