No abstract

The therapeutic effect of arsenic trioxide (As2O3 ) in the treatment of acute promyelocytic leukemia (APL) was evaluated among 15 APL patients at relapse after all-trans retinoic acid (ATRA) induced and chemotherapy maintained complete remission (CR). As2O3 was administered intravenously at the dose of 10 mg/d. Clinical CR was achieved in nine of 10 (90%) patients treated with As2O3 alone and in the remaining five patients treated by the combination of As2O3 and low-dose chemotherapeutic drugs or ATRA. During the treatment with As2O3 , there was no bone marrow depression and only limited side effects were encountered. Pharmacokinetic studies, which were performed in eight patients, showed that after a peak level of 5.54 μmol/L to 7.30 μmol/L, plasma arsenic was rapidly eliminated, and the continuous administration of As2O3 did not alter its pharmacokinetic behaviors. In addition, increased amounts of arsenic appeared in the urine, with a daily excretion accounting for approximately 1% to 8% of the total daily dose administered. Arsenic contents in hair and nail were increased, and the peak content of arsenic could reach 2.5 to 2.7 μg/g tissue at CR. On the other hand, a decline of the arsenic content in hair and nail was observed after withdrawal of the drug. We conclude that As2O3 treatment is an effective and relatively safe drug in APL patients refractory to ATRA and conventional chemotherapy.

NCT00874419.

It has been shown recently in China that arsenic trioxide (As2O3) is a very effective treatment for acute promyelocytic leukemia (APL). APL patients resistant to all-trans retinoic acid (ATRA) and conventional chemotherapy can still respond to AS2O3. In this study, we addressed the possible cellular and molecular mechanisms of this treatment by using NB4 cells as a model. The results show that: (1) As2O3 triggers relatively specific NB4 cell apoptosis at micromolar concentration, as proved by morphology, histogramic related nuclear DNA contents, and DNA gel eletrophoresis. (2) As2O3 does not influence bax, bcl-x, c-myc, and p53 gene expression, but downregulates bcl-2 gene expression at both mRNA and protein levels. (3) As2O3 induces a significant modulation of the PML staining pattern in NB4 cells and HL-60 cells. The micropunctates characteristic of PML-RAR alpha in NB4 cells dissappear after treatment with As2O3, whereas a diffuse PML staining occurs in the perinuclear cytoplasmic region. In addition, a low percentage of untreated NB4 cells exhibits an accumulation of PML positive particles in a compartment of cytoplasm. The percentage of these cells can be significantly increased after As2O3 treatment. A similar PML staining pattern is observed in apoptotic cells. (4) ATRA pretreatment does not influence As2O3-induced apoptosis. These results suggest that induction of cell apoptosis can be one of the mechanisms of the therapeutic effect of As2O3. Moreover, this apoptosis induction occurs independently of the retinoid pathway and may be mediated, at least partly, through the modulation of bcl-2, as well as PML-RAR alpha and/ or PML proteins.

Oral RIF plus ATRA is not inferior to intravenous ATO plus ATRA as first-line treatment of APL and may be considered as a routine treatment option for appropriate patients.

No abstract

It is of crucial importance to modify dextran-based polysaccharides in the design of novel biomedical materials. A simple one-step method, involving the reaction of hydroxyl groups of dextran with R-bromoisobutyric acid in the presence of 1,1 0 -carbonyldiimidazole, was first developed to produce bromoisobutyryl-terminated dextran as multifunctional initiators for subsequent atom transfer radical polymerization (ATRP). Well-defined comb-shaped copolymers (DPDs) composed of nonionic hydrophilic dextran backbones and cationic poly((2-dimethyl amino)ethyl methacrylate) (or P(DMAEMA)) side chains were subsequently prepared via ATRP for nonviral gene delivery. The P(DMAEMA) side chains of DPDs can be further partially quaternized to produce the quaternary ammonium DPDs (QDPDs). DPD and QDPDs can condense pDNA into complex nanoparticles of 100 to 150 nm in sizes. QDPDs exhibit stronger ability to complex pDNA, due to increased surface cationic charges. DPDs can exhibit much lower cytotoxicity and better gene transfection yield than high-molecular-weight P(DMAEMA) homopolymers and "gold-standard" polyethylenimine (25 kDa) in HEK293 and L929 cell lines. DPDs also exhibit efficient gene delivery ability in different cancer cell lines, especially in MCF7 cells where the DPD-mediated transfection efficiency is almost 3 times higher than that of the popular Lipfectamine 2000 transfection reagent. This study demonstrated that grafting low-molecular-weight polymer chains from natural dextran backbones via ATRP is an effective means to produce novel polysaccharide-based nanobiomaterials.

No abstract