Arsenic trioxide, a therapeutic agent for APL

Acute promyelocytic leukemia (APL) is an interesting model in cancer resear ch, because it can respond to the differentiation/apoptosis induction thera py using all-traps retinoic acid (ATRA) and arsenic trioxide (As2O3). Over the past 5 years, it has been well demonstrated that As2O3 induces a high c omplete remission (CR) rate in both primary and relapsed APL patients (arou nd 85 similar to 90%). The side effects are mild to moderate in relapsed pa tients, while severe hepatic lesions have been found in some primary cases. After CR obtained in relapsed patients, chemotherapy in combination with A s2O3 as post-remission therapy has given better survival than those treated with As2O3 alone. The effect of As2O3 has been shown to be related to the expression of APL-specific PML-RAR alpha oncoprotein, and there is a synerg istic effect between As2O3 and ATRA in an APL mouse model. Cell biology stu dies have revealed that As2O3 exerts dose-dependent dual effects on APL cel ls. Apoptosis is evident when cells are treated with 0.5 similar to2.0 muM of As2O3 while partial differentiation is observed using low concentrations (0.1 similar to0.5 muM) of the drug. The apoptosis-inducing effect is asso ciated with the collapse of mitochondrial transmembrane potentials in a thi ol-dependent manner, whereas the mechanisms underlying APL cell differentia tion induced by low dose arsenic remain to be explored. Interestingly, As2O 3 over a wide range of concentration (0.1 similar to2.0 mum) induces degrad ation of a key leukemogenic protein, PML-RAR alpha, as well as the wild-typ e PML, thus setting up a good example of targeting therapy for human cancer s.