As2O3 Sensitivity in Acute Promyelocytic Leukemia and Refractory Acute Leukemia

Lee, Seungok; Kim, Myungshin; Lim, Jihyang; Kim, Yonggoo; Han, Kyungja; Lee, Kyo Young; Kang, Chang Suk

Abstract

BACKGROUND
Inorganic arsenic trioxide (As2O3) has emerged as a new drug of choice for refractory acute promyelocytic leukemia (APL). But, the curable disease spectrum and the arsenic resistance in association with the expression of multidrug resistance (MDR) proteins are not yet to be established. METHODS: Five de novo APL and 20 refractory acute leukemia cases were selected. Leukemic cells were cultured for 24 hr in media with various As2O3 concentrations. Apoptotic cells or damaged cells were measured by a morphologic examination after Wright stain and flow cytometry using annexin V/propidium iodide (PI) stain. The lowest concentration of As2O3 at which greater than 90% of leukemic cells were damaged morphologically was defined as the morphologic arsenic sensitivity of leukemic cells. MDR protein markers including multidrug resistance associated protein (MRP), lung resistance protein (LRP), P-glycoprotein (PGP) and glutathinoe-S-transferase (GST) were analyzed by flow cytometry. RESULTS: The leukemic cells from de novo APLs (in 3 of 5) were sensitive to arsenic trioxide, compared to refractory acute leukemia (only 1 of 20). Of the five MDR proteins examined, only PGP was expressed more in the arsenic resistant cases (in 8 of 21) than in the sensitive cases (none of 4) (P=.032). CONCLUSIONS: Refractory acute leukemia had a variable arsenic sensitivity, but were more resistant than de novo APL. The arsenic resistance seems to be related to PGP expression.