Combination Therapy with Arsenic Trioxide for Hematological Malignancies

Shinichiro      Takahashi

Abstract

Arsenic trioxide (ATO) has shown great promise in the treatment of patients with relapsed or refractory acute promyelocytic leukemia (APL). However, the risk/benefit ratios of ATO in hematologic malignancies other than APL are still unclear. In this review, the author attempts to provide current experimental and clinical challenges to gain more knowledge of the effects of ATO by examining combination therapies with other agents, especially for non-APL hematologic malignancies, such as acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphoid leukemia (CLL) and multiple myeloma (MM). The drugs combined with ATO can be roughly classified into (1) signaling inhibitors (imatinib, PD184352, LY294002, 17-Allylamino- 17-demethoxygeldanamycin: 17-AAG), (2) oxidative stress pathway modulators (ascorbic acid, 2-methoxyestradiol: 2-ME, dlbuthionine-[ S,R]-sulfoximine: BSO), (3) a chemotherapeutic drug (melphalan) and (4) others (bortezomib, ATRA). Some of these combination therapies have shown promising results in MM not only at the experimental level but also at the clinical level. However, studies are still ongoing for other non-APL hematologic malignancies. Since ATO is well tolerated and its toxicities are manageable and reversible, cell type-specific and efficient combination therapies with ATO are advantageous for non-APL hematological malignancies and should be developed in the near future.

Keywords: Acute lymphoid leukemia, acute myeloid leukemia, arsenic trioxide, chronic lymphoid leukemia, chronic myeloid leukemia, combination therapy, multiple myeloma, Hematological Malignancies, acute promyelocytic leukemia, imatinib, PD184352, LY294002, 17-Allylamino-17-demethoxygeldanamycin, oxidative stress pathway modulators, ascorbic acid, 2-methoxyestradiol, dlbuthionine-[S,R]-sulfoximine, potassium bicarbonate, Thomas Fowler's solution, all-trans retinoic acid, promyelocytic leukemia, retinoic acid receptor a, myeloma cells, MYELODYSPLASTIC SYNDROME, hematologic malignancies, extracellular signal-regulated kinase, Fms-like tyrosine kinase 3, glucocorticoid-resistant ALL cells, antineoplastic agents, Bcr-Abl-positive leukemic cells, cytochrome c, NF-κB, IκB kinase, small ubiquitin-like protein modifier (SUMO)-conjugating enzyme 9, SUMOylation