Fifty-eight acute promyelocytic leukemia (APL) patients (11 newly diagnosed and 47 relapsed) were studied for arsenic trioxide (As2O3) treatment. Clinical complete remission (CR) was obtained in 8 of 11 (72.7%) newly diagnosed cases. However, As2O3 treatment resulted in hepatic toxicity in 7 cases including 2 deaths, in contrast to the mild liver dysfunction in one third of the relapsed patients. Forty of forty-seven (85.1%) relapsed patients achieved CR. Two of three nonresponders showed clonal evolution at relapse, with disappearance of t(15;17) and PML-RAR fusion gene in 1 and shift to a dominant AML-1-ETO population in another, suggesting a correlation between PML-RAR expression and therapeutic response. In a follow-up of 33 relapsed cases over 7 to 48 months, the estimated disease-free survival (DFS) rates for 1 and 2 years were 63.6% and 41.6%, respectively, and the actual median DFS was 17 months. Patients with white blood cell (WBC) count below 10 × 109/L at relapse had better survival than those with WBC count over 10 × 109/L (P = .038). The duration of As2O3-induced CR was related to postremission therapy, because there was only 2 of 11 relapses in patients treated with As2O3 combined with chemotherapy, compared with 12 of 18 relapses with As2O3 alone (P = .01). Reverse transcription polymerase chain reaction (RT-PCR) analysis in both newly diagnosed and relapsed groups showed long-term use of As2O3 could lead to a molecular remission in some patients. We thus recommend that ATRA be used as first choice for remission induction in newly diagnosed APL cases, whereas As2O3 can be either used as a rescue for relapsed cases or included into multidrug consolidation/maintenance clinical trials.

Imatinib (STI571, Gleevec) is a tailored drug for chronic myelogenous leukemia (CML), whereas arsenic compounds were used as ancient remedies for CML with certain efficacy. The aim of this study was to investigate the potential benefit of combination therapy with imatinib and arsenic sulfide (As 4 S 4 ). Analysis of cell proliferation and clonogenic ability showed that As 4 S 4 and imatinib exerted synergistic effects on both K562 cells and fresh CML cells. The effective concentrations on fresh CML cells were pharmacokinetically available in vivo but had much less inhibitory effect on CD34 ؉ cells from the nonleukemic donors. Examination of cell cycles showed that As 4 S 4 induced G 2 /M arrest whereas imatinib induced G 1 arrest. Using a number of parameters such as morphology, annexin V/propidium iodide (PI), mitochondrial transmembrane potential, caspase-3 activity, and Fas/ Fas-L, the synergistic effects were revealed on induction of cell apoptosis, largely through the mitochondrial pathway. The 2 drugs also exhibited a synergistic effect in targeting BCR-ABL protein. While As 4 S 4 triggered its degradation and imatinib inhibited its tyrosine kinase activity, combined use of the 2 led to lower protein/enzymatic activity levels of BCR-ABL. Our in vitro data thus strongly suggest a potential clinical application of imatinib and As 4 S 4 combination on CML. IntroductionChronic myeloid leukemia (CML) is a clonal pluripotent hematopoietic stem cell disorder. Leukemic cells from more than 95% of patients with CML carry the Philadelphia (Ph) chromosome, resulting from t(9;22) reciprocal chromosome translocation, and express a BCR-ABL fusion protein with a relative molecular mass of 210 kDa. BCR-ABL protein has more potent tyrosine kinase activity than the wild-type 145-kDa ABL, leading its downstream signal molecules to be phosphorylated and activated, constituting the molecular basis of CML, 1-3 although the critical pathways of CML still remain to be further defined. Targeted treatment against BCR-ABL and/or its downstream effector molecules has become a new hot spot and the introduction of imatinib (STI571, Gleevec, CGP57148B) into CML treatment during the past few years represents the most significant example in this progress. [4][5][6][7] Imatinib competes the adenosine triphosphate (ATP) binding site of the kinase domain of ABL, which allows a selective inhibition of the action of BCR-ABL and thereby blocks the activation of its downstream effector molecules. 8 Clinical trials have shown that imatinib has very good effects on patients with chronic phase (CP), but its effects on patients with accelerated phase or blast phase (advanced phase, AP) are unsatisfactory since many patients relapse after transient remission. [9][10][11][12] In addition, even among patients at CP, imatinib seems unable to eradicate the malignant progenitors and a significant portion of patients develops drug resistance after long-time use. [13][14][15][16] Hence, to improve response rates and to circumvent resistance, additional dru...