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

Abstract Arsenic compounds, including arsenic trioxide (As 2 O 3 ) and arsenic sulfide (As 4 S 4 ), have recently been shown to be effective in the treatment of acute promyelocytic leukemia (APL). In vitro, As 2 O 3 exerts a dosedependent dual effect: it triggers apoptosis at relatively high concentrations (0.5 to 2.0 μmol/L) and induces partial differentiation at low concentrations (0.1 to 0.5 μmmol/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. As 2 O 3 over a wide range of concentrations (0.1 to 2.0 μmol/L) induces degradation of PML-RARα as well as the wild-type PML and enhances the acetylation of histone, a process important for the transcriptional activation of genes. In vivo, As 2 O 3 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 As 2 O 3 as postremission therapy has yielded better survival than treatment with As 2 O 3 alone. This is in line with the observation that remission induction with As 2 O 3 is not sufficient in most cases to obtain a molecular remission as judged by reverse-transcriptase polymerase chain reaction for PML-RARα fusion transcripts. The in vivo effect of As 2 O 3 seems to be related to the expression of APL-specific PML-RARα oncoprotein, and a synergistic effect between As 2 O 3 and ATRA has been shown in the APL mouse model. Besides As 2 O 3 , other arsenic compounds such as As 4 S 4 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 As 2 O 3 can be incorporated into multidrug postremission therapy or used as rescue for relapsed APL patients.