Arsenic trioxide: acute promyelocytic leukemia and beyond

Arsenic containing treatments have a history of over two millenniums. Recently, arsenic trioxide (As2O3) has been introduced into the treatment of both de now and relapsed acute promyelocytic leukemia (APL), with remarkable clinical success. Several investigations using both freshly isolated APL blast cells as well as APL-derived tumor cell lines have shown that the main mechanism by which As2O3 exerts its antileukemic activity in APL is induction of apoptosis in the leukemic cell population. Recently, it has become evident that the apoptotic effects of As2O3 are not restricted to APL cells but may also be observed in malignant cells of non-APL origin. In the present review, history, current clinical use as well as future perspectives of As2O3 therapy in both hematologic and solid malignancies are discussed, with special emphasis being put on the potential future role of As2O3 in the treatment of non-APL tumors. Of particular importance, enhancing agents suited to increase As2O3-sensitivity in less sensitive tumors (e.g. ascorbic acid) are also addressed.