br The following are clinical situations in which the use

The following are clinical situations in which the use of an As2O3 regimen may be indicated [6–9]: 1) Previously untreated (or newly diagnosed) APL especially in patients who are positive for t(15;17) or the PML/RARα/PML-fusion gene, a key feature in more than 90% of such patients; 2) APL that is refractory to all-trans retinoic GSK1120212 (RA) or combined chemotherapy, recurrent disease, or relapsed after bone marrow transplantation; 3) APL in patients for whom RA and combined chemotherapy are intolerable or inadvisable; 4) Maintenance treatment after CR from APL; and 5) CGL and certain acute nonlymphocytic leukemia subtypes as well as those with myelodysplastic syndromes (MDS), if these are accompanied by an excessive increase in the number of promyelocytes. As2O3 treatment is not suitable for a first choice for some APL patients, such as positivity for either t(11;17),t(5;17) or for the PLZF/RARα fusion gene, moderate to severe liver or kidney dysfunction caused by conditions other than leukemia, relapse during continuous As2O3 maintenance treatment or long-term arsenic exposure [8,9].
Methods of treatment
Shen et al. [11]. administered As2O3 intravenously at a dose of 10mg/day for the treatment of 8 patients with relapsed APL. The arsenic content was measured by gas-phase chromatography. The maximal plasma concentration was 0.94±0.37mg/L, the time to peak concentration was 4h, the plasma distribution half-time was 0.89±0.29h, the elimination half-time was 12.13±3.31h, the a apparent distribution volume was 3.83±0.45L, the system clearance was 1.43±0.17L/h, and the area under the curve was 7.25±0.97L/h. The continuous administration of As2O3 did not alter its pharmacokinetic behavior. During As2O3 treatment, the 24-h arsenic content in urine accounted for 1–8% of the daily dose. The arsenic accumulation in the hair and nails increased continuously, with a peak concentration rose 5- to 7-fold higher than pretreatment levels. Importantly, the arsenic content of urine, hair, and nails declined gradually after drug withdrawal. No bone marrow suppression or severe organ impairment were observed. The researchers concluded that As2O3 is a relatively safe and effective for the treatment of patients with relapsed APL, despite the arsenic accumulation in some tissues. Hu et al. [12]. found that arsenic content in the cerebrospinal fluid was 4.8±0.4μg/L in 40 healthy people, comparatively, the content in patients before and 12h after treatment with a routine dose of As2O3 was 4.8±0.3μg/L and 5.2±0.1μg/L, respectively. Similarly, in 46 patients with APL, no significant difference was found between these groups (p>0.05). However, 12h after treatment, the arsenic content in peripheral blood (30.0±5.0μg/L) was significantly higher than that of cerebrospinal fluid (p<0.01), suggesting that it is inadvisable to use intravenous As2O therapy for patients with central nervous system (CNS) leukemia.
Factors related to therapeutic effectiveness Therapeutic effectiveness and prognosis have a positive correlation with the band-cell count of peripheral WBC, hemoglobin content, platelet count, and bone marrow normoblast count. We found a negative correlation with WBC count, peripheral juvenile blood cell count, myeloproliferation degree, and lactic dehydrogenase (LDH) activity [8,9].
Drug resistance In clinical practice, there is no cross–drug-resistance between As2O3 and RA or other antileukemic agents. This may be explained by the non-liposoluble nature of As2O3, its small molecular weight, and its distinctive modes of action [20]. In our observation, primary As2O3 resistance was found in 35.9% of refractory patients, 15.3% of patients whose disease relapsed after nonarsenic induction and consolidation, and in 5.7% of newly diagnosed APL patients; the rate of acquired resistance to As2O3 was 26.7% (23/86). In the latter instance, an increased dose of As2O3 enabled more than half of resistant patients to regain CR, presumably through overcoming an “inertia” in arsenic receptor or signaling pathways [9]. Geng et al. [21] found cross–drug-resistance between As2O3 and cisplatin. An increased As2O3 dose or action time resulted in a decrease of multidrug resistance protein expression and reversed the resistance.
Toxicity and side effects
As2O3 treatment was recently proposed as an alternative therapy for APL, because it can induce CR in patients with either RA-sensitive or RA-resistant APL. Intriguingly, As2O3 was also induced degradation of PML/RARα chimeras and to reorganize PML nuclear bodies（PML-NBs） [30]. In APL patients, RA triggers differentiation, whereas As2O3 induces both a partial differentiation and apoptosis. Although their mechanisms of action are believed to be distinct, both drugs induce catabolism of the oncogenic PML/RARα-fusion protein. Although APL cell lines resistant to one of these agents are sensitive to the other, the benefit of combining RA and arsenic in cell culture remains controversial. Shao et al. [31] believe that As2O3 and RA inhibit each other，s therapeutic effects.