Arsenic and Apoptosis in the Treatment of Acute Promyelocytic Leukemia

Extract

Remarkable progress has been made in identifying the oncogenic fusion proteins that are produced as a result of specific chromosomal translocations in the human acute leukemas (1). Because these proteins are expressed only by cells within the leukemic clones, they hold great promise as targets for new drugs that will specifically destroy leukemic cells while leaving normal cells unharmed. Both all-trans-retinoic acid (t-RA) and arsenic trioxide (As₂O₃) have shown this type of activity in patients with acute promyelocytic leukemia (APL) whose blast cells harbor the t(15;17) chromosomal translocation and express the PML/RARα fusion protein Each of these agents was identified empirically in innovative clinical trials conducted by investigators at the Shanghai and Harbin Institutes of Hematology in China (2,3) A plausible biochemical basis for the selective action of t-RA became apparent once the PML/RARo fusion gene was cloned, since the aberrant protein contains the retinoic binding domain of retinoic acid receptor (RARa (4–8). Subsequent work showed that t-RA can induce differentiation of leukemic promyelocytes (2,9–11), and clinical trials combining r-RA with standard cytotoxic drugs have led to improved survival in patients with APL (12–16).