The aim of this study was to determine the efficacy and safety of treatment of pediatric acute promyelocytic leukemia (APL) with single-agent arsenic trioxide (ATO). A total of 19 children (< 15 years of age) with newly diagnosed APL were treated with single-agent ATO for remission induction and postremission therapy. Seventeen of the children (89.5%) achieved complete hematologic remission, and 2 early deaths occurred from intracranial hemorrhage. ATO-induced leukocytosis was observed in 13 (68.4%) patients. Other ATO-related toxicities were minimal and transient. Postremission ATO therapy continued for 3 years; the most common side effect was ATO-induced neutropenia. With a median follow-up of 53 months (range, 23-76 months), the calculated 5-year overall survival and eventfree survival were 83.9% and 72.7%, respectively, which are comparable with results achieved by the use of ATRA plus chemotherapy, which is the standard therapy for APL. No chronic arsenic toxicity or second malignancies were found during the follow-up period, and arsenic retention was not significant in patients off treatment more than 24 months. IntroductionAcute promyelocytic leukemia (APL) accounts for approximately 10% of childhood acute myeloid leukemia. [1][2][3][4] APL is characterized by the French-American-British M3 subtype morphology, a distinctive immunophenotype, and, in the majority of cases, there is a t(15;17) chromosomal translocation that generates the promyelocytic leukemia-retinoic acid receptor-␣ (PML-RARa) fusion gene. This specific genetic lesion determines the unique response to treatment with all-trans retinoic acid (ATRA) or arsenic trioxide (ATO). 5 Since the introduction of ATRA in the 1980s and ATO in the 1990s, the strategy for treating APL has shifted from conventional chemotherapy to cancer cell differentiation and cancer-targeted therapy. The combination of ATRA and anthracycline-based chemotherapy is currently the standard approach to treat newly diagnosed APL. With this regimen, the hematologic complete remission (HCR) rate has improved significantly, to more than 90%; 5-year disease-free survival is more than 70%. 5-10 However, some problems still remain; notably, ATRA-related side effects appear to be more pronounced in children than in adult patients, 4,11-13 the optimal postremission therapy still remains to be defined, and approximately 20% to 30% of patients eventually relapse and develop drug resistance.ATO has proven to be another highly effective agent in APL therapy. 14-21 ATO differs from ATRA because of its dual effects of inducing partial differentiation and apoptosis of APL cells. Although highly efficacious, ATO is most commonly used in refractory or relapsed APL for inducing remission. It has previously been shown that single-agent ATO is equally effective in inducing remission in newly diagnosed cases of adult APL. However, little is known about the use of single-agent ATO in the treatment of children with APL. The optimal dosage and route of administration during remission induction and ...

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Regulation and function of PI 3K/Akt and mitogen-activated protein kinases (MAPKs) in doxorubicin-induced cell death were investigated in human lung adenocarcinoma cells. Doxorubicin induced dose-dependent apoptosis of human lung adenocarcinoma NCI-H522 cells. Prior to cell death, both Akt and the MAPK family members (MAPKs: ERK1/2, JNK, and p38) were activated in response to the drug treatment. The kinetics of the inductions for Akt and MAPKs are, however, distinct. The activation of Akt was rapid and transient, activated within 30 min of drug addition, then declined after 3 h, whereas the activations of three MAPKs occurred later, 4 h after addition of the drug and sustained until cell death occurred. Inhibition of PI 3K/Akt activation had no effect on MAPKs' activation, suggesting that the two pathways are independently activated in response to the drug treatment. Inhibition of PI 3K/Akt and p38 accelerated and enhanced doxorubicin-induced cell death. On the contrary, inhibition of ERK1/2 or JNK had no apparent effect on the cell death. Taken together, these results suggest that PI 3K/Akt and MAPKs signaling pathways are all activated, but with distinct mechanisms, in response to doxorubicin treatment. Activation of PI 3K/Akt and p38 modulates apoptotic signal pathways and inhibits doxorubicin-induced cell death. These responses of tumor cells to cancer drug treatment may contribute to their drug resistance. Understanding of the mechanism and function of the responses will be beneficial for the development of novel therapeutic approaches for improvement of drug efficacy and circumvention of drug resistance.