Might arsenic trioxide be useful in the treatment of advanced myelodysplastic syndromes?

Failure of conventional therapies is dramatic in patients with advanced myelodysplastic syndromes (MDS), thus therapeutic approaches that increase the apoptotic rate of myelodysplastic syndrome (MDS) cells might be advantageous. We studied the behavior of cells exposed to As2O3 in vitro from patients with advanced MDS. Our data show that therapeutically useful concentrations of As2O3 increase the rate of apoptosis in short-term cultures. Moreover, pre-treatment with GM-CSF increased the sensitivity of the cells to the effect of As2O3. Sir, The search for therapy of myelodysplastic syndromes has so far been unsuccessful. Single agent chemotherapy as well as acute myeloid leukemia (AML)-type chemotherapy, alone or in combination with human growth factor (HGF), have not shown a clear beneficial effect on survival in MDS or in MDS-related AML. Morphologic features of apoptosis are easily demonstrable in MDS cell populations. 1 Moreover, data about fas expression in CD34 + MDS cells show that the myeloblast populations that emerge with disease progression are more resistant to fas-induced cell death. 2 Thus, it is possible to hypothesize that, in advanced phases of MDS, an increase in the apop-totic rate of MDS cell populations might be advantageous. Recently, much attention has been drawn to the use of As2O3 as a useful agent in the treatment of AML-M3 that has become resistant to standard retinoic acid treatment. 3 In a patient with retinoic-resistant AML-M3 treated with arsenic trioxide we observed a very good correspondence between the levels of drug-induced apoptosis in affected cells in vivo and that observed in vitro in liquid culture. This correspondence was maintained during progression of the disease (4 and AD, personal communication). In the present study, we collected blood samples from 14 patients with the diagnoses shown in Table 1. Bone marrow or peripheral mononuclear cells were seeded in 6-well plates (250,000 cells/mL IMDM/10% FCS). After 24 hours, As2O3 was added at concentrations of 0.1, 0.5, 1 and 2 µM. After 5 days in culture, culture aliquots were stained with propidium iodide and analyzed by FACS using Lysis II software. The percentage of cells in the hypodiploid peak was used to assess the percentage of apoptotic cells. A minimum of 10,000 events were taken for each sample. The result obtained show that micromolar concentrations of As2O3 were effective at inducing apop-tosis in 7/11 advanced MDS cases. No apoptosis was induced in cases of AML-M0 and Ph+ALL. We also observed that the drug was …