Association of nitric oxide synthase 3 (NOS3) 894 G>T polymorphism with prognostic outcomes of anthracycline in Chinese patients with acute myeloid leukaemia.

The aim of the present study was to investigate the influence of the nitric oxide synthase 3 (NOS3) 894 G>T polymorphism on prognostic outcomes of anthracycline in Chinese patients with de novo intermediate-risk acute myeloid leukaemia (AML) and to examine the gene expression level in relation to genetic variation. In all, 225 Chinese patients with intermediate-risk AML (at the complete remission stage) treated with anthracycline were enrolled in the study. The 894 G>T polymorphism of the NOS3 gene was analysed by allele-specific matrix-assisted laser desorption ionization time-of-flight. Expression of NOS3 mRNA was tested in 72 patients of known genotype for NOS3 894 G>T. The clinical characteristics of these patients were obtained from medical records. Survival analysis showed that patients with AML (GG genotype) had a longer overall survival (OS; P = 0.006). After adjusting for age, gender, leucocyte count, haemoglobin level, platelet level, French, American and Britain (FAB) classification, lactate dehydrogenase levels, Eastern Cooperative Oncology Group Performance Status, nucleophosmin gene and fms-related tyrosine kinase 3 gene, multivariate survival analysis showed that the NOS3 894 G>T polymorphism appeared to be a predicting factor for OS (P = 0.014; hazard ratio = 1.856). However, no significant associations between the NOS3 894 G>T polymorphism and relapse-free survival and relapse in patients with AML were observed. Gene expression levels were significantly higher in patients with the GG genotype than in patients with the GT and TT genotypes (P = 0.033). The findings suggest that the NOS3 894 G>T variant may be a biomarker for the prediction of OS in Chinese patients with AML.

Reversion of Multidrug-Resistance by Proteasome Inhibitor Bortezomib in K562/DNR Cell Line.

OBJECTIVE: To observe the reversion of multi-drug resistance by proteasome inhibitor bortezomib in K562/DNR cell line and to analyze the possible mechanism of reversion of multidrug-resistance. METHODS: MTT method was used to determine the drug resistance of K562/DNR cells and the cellular toxicity of bortezomib. K562/DNR cells were cultured for 12 hours, 24 hours and 36 hours with 100 µg/ml DNR only or plus 4 µg/L bortezomib. The expressions of NF-κB, IκB and P-gp of K562/DNR were detected with Western blot method, the activity of NF-κB was tested by ELISA method and the apoptosis rate was observed in each group respectively. RESULTS: The IC50 of DNR on cells of K562/S and K562/DNR groups were 1.16 µg/ml and 50.43 µg/mL, respectively. The drug-resistant fold was 43.47. The IC10 of PS-341 on Cell strain K562/DNR was 4 µg/L. Therefore, 4 µg/L was selected as the concentration for PS-341 to reverse drug-resistance in this study. DNR induced down-regulation of IκB expression, up-regulation of NF-κB and P-gp expression. After treatment with PS-341, a proteasome inhibitor, the IκB degradation was inhibited, IκB expression increased, NF-κB and P-gp expression decreased in a time dependent manner. Compared to DNR group, the NF-κB p65 activity of DNR+PS-341 group was decreased. Compared to corresponding DNR group, DNR induced apoptosis rate increases after addition of PS-341 in a time dependent manner. CONCLUSION: Proteasome inhibitor bortezomib can convert the leukemia cell drug resistance. The mechanism may be that bortezomib decreases the degradation of IκB and the expression of NF-κB and P-gp, therefore induces the apoptosis of multi-drug resistant cells.

Enlarged and prominent nucleus may be indicative of tetraploidy: a laboratory study of a rare near-tetraploidy in a child patient with acute myelogenous leukemia AML-M4.

SUMMARY: Near-tetraploidy is a rare cytogenetic abnormality in myelocytic malignancies in children and its significance is unknown. To investigate the pathologic characteristics of a near-tetraploidy in a child with acute myelogenous leukemia (AML-M4), bone marrow smears were prepared for morphologic analysis. Bone marrow samples were collected at presentation for flow cytometry, prepared by short-term (24 h) unstimulated culture and R-banding for conventional cytogenetic assay. We have performed a multifactorial analysis of the laboratory test results. In this case, the chromosomal analysis (R-banding) demonstrated a near-tetraploidy. Combined with morphologic and immunophenotypic results, the diagnosis was established as acute myelogenous leukemia (AML-M4). Near-tetraploidy is an uncommon cytogenetic finding, and the experience of this case further emphasizes the importance of the laboratory diagnostic methods.

[MiR-199a-5p Affects Sensitivity of Acute Myeloid Leukemia to Adriamycin by Targeting DRAM1].

OBJECTIVE: To compare the expression of miR-199a-5p between ADM-resistant AML cell (K562/ADM)and ADM-sensitive AML cell (K562), and to investigate the effect of miR-199a-5p on regulating AML drug resistance as well as its molecular mechanism. METHODS: MTT method was used to detect the proliferation inhibition effect of ADM on K562 and K562/ADM cells, the IC50 was calculated. miR-199a-5p expression in cell lines (K562 and K562/ADM) and bone marrow sample (refractory/relapsed AML patients and complete remission AML patients) was detected by RT-qPCR. K562/ADM and K562 cells were transfected by miR-199a-5p mimic and miR-199a-5p inhibitor respectively to ensure that miR-199a-5p expression in K562/ADM cells was increased and that in K562 cells was decreased. Then proliferation inhibition effect of ADM on both cells was detected by CCK-8 and mRNA and protein DRAM1 expression in both cells was measured by real time RT-PCR and Western blot respectively. Dual luciferase reporter assay was used to detect wether there were direct binding sites between miR-199a-5p and DRAM1 3' UTR. CCK-8 was used to measure the proliferation inhibition effect of ADM on K562/ADM cells when DRAM1 was downregulated by siRNA. RESULTS: The IC50 of ADM for K562/ADM and K562 cells was 146.14±0.079 and 3.08±0.056 µg/ml respectively. As compared with patients in complete remission group, MiR-199a-5p expression in refractory/ relapsed AML patients significantly decreased, and the MiR-199a-5p expression in K562/ADM cells was also dramatically downregulated, compared with K562 cells (P＜0.05). When the expression of miR-199a-5p was upregulated in K562/ADM cells, the proliferation inhibition effect of ADM on cells elevated and both DRAM1 mRNA and protein expressions decreased. Conversely, when miR-199a-5p expression was downregulated in K562 cells, the proliferation inhibition effect of ADM on cells obviously reduced and both DRAM1 mRNA and protein expression increased (P＜0.05). Dual luciferase reporter Assay showed a direct interaction between miR-199a-5p and its binding site within DRAM1 mRNA. Both DRAM1 mRNA and protein expression in K562/ADM were markedly higher than those in K562 cells (P＜0.05). The ADM chemosensitivity of K562/ADM cells was improved significantly when DRAM1 expression was downregulated (P＜0.05). CONCLUSION: miR-199a-5p is downregulated in chemoresistant AML cells. miR-199a-5p expression plays an important role in regulating the sensitivity of AML cells to ADM treatment. DRAM1 is a functional target gene for miR-199a-5p modulating AML chemoresistance.

Laboratory study on near-tetraploid acute myelogenous leukemia of childhood.

Near-tetraploidy is a rare cytogenetic abnormality in myelocytic malignancies in children, and its significance is unknown. To investigate the characteristics of near-tetraploidy in a child with acute myelogenous leukemia (AML-M4), bone marrow smears were prepared for morphological analysis. Bone marrow samples were collected for flow cytometry, and prepared by short-term (24 hrs) unstimulated culture and R-banding for conventional cytogenetic assay. In this case, the morphological analysis of bone marrow cells showed large and prominent nuclei. The chromosomal analysis (R-banding) demonstrated a near-tetraploidy. Combined with morphological and immunophenotypic results, AML-M4 was confirmed. The patient was given four cycles of chemotherapy, and finally achieved clinical remission. However, the duration achieving the remission in the child was longer than AML children with normal karyotype. It is believed that near-tetraploid karyotype may have a great significance to the therapy and prognosis.

[Research Progress on Multiple Myeloma-Related Cardiovascular Events--Review].

Abstract　　The patients with multiple myeloma are often accompanied by cardiovascular injuries, that not only related with age, but also with the disease itself and treatment. Timely detection and proper supervision of cardiovascular injuries in patients will reduce the mortality of patients with multiple myeloma. In this review, the pathophysiology, diagnosis and treatment of cardiovascular damages in patients with multiple myeloma are summarized briefly, so as to provide some references for clinical treatment and research.

[Role of Reactive Oxygen Species in GDC-0152-Induced Apoptosis and Autophagy of NB4 cells].

OBJECTIVE: To investigate the effect of reactive oxygen species (ROS) on GDC-0152-induced apoptosis and autophagy of acute promyelocytic leukemia cell line NB4. METHODS: Different concentrations of GDC-0152 combined with Z-VAD-FMK was applied to NB4 cells. Cell proliferation was detected by CCK8 method. Apoptosis rate, autophagy and ROS level were detected by flow cytometry. The autophagy was observed by Cyto-ID staining fluorescence microscopy, and flow cytometry were used to detect the fluorescence expression. The expression of autophagy-related protein LC3B was detected by Western blot. RESULTS: GDC-0152 increased proliferation inhibition rate and apoptosis rate in NB4 cells (P＜0.05); GDC-0152 induced increase of ROS level of NB4 cells; GDC-0152 increased autophagy of NB4 cells that was found by Cyto-ID staining fluorescence microscopy and flow cytometry (P＜0.05). Western blot showed that GDC-0152 increased LC3B expression in NB4 cells and promoted the conversion of LC3BI to LC3BII; as compared with GDC-0152 (100 ng/ml), GDC-0152 (100 ng/ml) combined with ROS inhibitor YCG063 (10 µmol/L) decreased apoptosis and autophagy (P＜0.05). CONCLUSION: GDC-0152 inhibits cell proliferation by inducing apoptosis and autophagy of NB4 cells. ROS can promote GDC-0152-induced apoptosis and autophagy of NB4 cells.

Interdigitating dendritic cell sarcoma located in the groin: a case report and literature review.

Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare subtype of dendritic cell neoplasms, and current knowledge on this tumor is limited. We herein report a case of an IDCS in a 64-year-old man who presented with a right inguinal mass combined with extensive retroperitoneal, pulmonary, hepatic, renal, and bone marrow infiltration. Because of the advanced stage of the disease, we performed five cycles of chemotherapy, including cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); and ABVD combined with cisplatin, and one cycle of radiotherapy. The patient's inguinal mass became smaller during the treatment, but there was no change in the extent of infiltration at the other sites. The patient died 8 months after the initial diagnosis. We also herein review the etiology, diagnosis, differential diagnosis, treatment, and prognosis of IDCS, and analyze the characteristics of IDCS in Chinese patients.

[Embelin Reverses the Multi-drug Resistance of K562/D to Daunorubicin Independently of P-gp and MDR1 mRNA].

OBJECTIVE: To investigate the mechanism of reversing drug resistance of K562/D cells to daunorubicin by Embelin and its relationship with P-gp and MDR1 mRNA. METHODS: MTT assay was used to detect and compare the cell proliferation rate of treating with DNR alone and DNR combined with Embelin. Flow cytometry with Annexin V-FITC/PI double staining was used to detect cell apoptosis rate, Western blot was used to detect the expression of XIAP,Caspase-3,BCL-2,BAX and P-gp of K562/D cells after using DNR alone and combining with Embelin. Quantitative real-time PCR was used to detect XIAP,BCL-2,BAX and MDR1 mRNA. RESULTS: The IC50 of K562 and K562/D cells treated with DNR for 24 h were 2.177 µg/ml and 69.43 µg/ml, respectively. The drug-resistance index was 31.89; The proliferation inhibition rates of K562/D cells treated with Embelin of 3, 10, 30, 100 and 300 µg/ml for 24 h were 2.70%±1.08%, 10.92%±4.89%, 28.13%±2.09%, 36.56%±3.24% and 43.59%±1.16%; The proliferation inhibition rates of K562/D cells treated with DNR of 0.1, 1, 10 and 100 µg/ml combined with 10 µg/ml Embelin for 24 h were 31.92%±3.29%, 49.57%±6.87%, 55.16%±0.78% and 71.94%±3.89%. The IC50 was 2.11 µg/ml respectively. The reverse index was 32.91. The apoptosis rates of K562/D cells treated with 0.1 µg/ml DNR alone or combined with Embelin of 10 µg/ml and 30 µg/ml for 24 h were 12.06%±0.95%, 27.54%±0.59% and 39.59%±1.57%, respectively. The results of Western blot showed that after combination of DNR with Embelin, the expression of Caspase-3 was significantly down-regulated (P<0.05), moreover, the prolifiration inhibition effect of drug combination on cells could be countreacted by Z-VAD-FMK, at the same time the expression of XIAP and BCL-2 protein was significantly down-regulated(P<0.05), the expression of BAX protein was significantly up-regulated(P<0.05), while there was no change of P-gp expression later (P<0.05). The results of RT-PCR showed that after combination of DNR with Embelin, expression of XIAP and BCL-2 mRNA was significantly down-regulated(P<0.05), expression of BAX mRNA was significantly up-regulated(P<0.05), while there was no obvious change of MDR1 mRNA expression(P>0.05). CONCLUSION: The down-regulation of XIAP contributes to enhance the effect of DNR on K562/D cells, the mechanism of Embelin-reversing the drug-resistence of K562/D cells to DNR does not relate with P-gp and MDR1 mRNA.

Can body mass index predict the outcome of diffuse large B-cell lymphoma? A single-center retrospective study in China.

We carried out a single-center retrospective study to assess the predictive value of body mass index (BMI) in the outcome of Chinese patients with diffuse large B-cell lymphoma (DLBCL). 143 eligible patients were enrolled between January 2008 and May 2015. These patients were stratified into two groups, 74 patients in low BMI group (BMI <23.0 kg/m2) and 69 patients in high BMI group (BMI ≥23.0 kg/m2). We compared the baseline characteristics, primary response, and survival outcome in two groups. Well-known influence factors were similar between the two groups, while gender was not (p = .023) but did not act as a risk factor. No association between BMI and primary response was observed. Patients with high BMI were inclined to have better overall survival (OS) (p = .018), but we didn't find an association in progression-free survival (PFS) (p = .067). We also found a sex-dependent effect of BMI on OS, with high BMI increased OS in female patients (p = .027) but showed no correlation in male patients (p = .310).

[CAR Technology and Its Application in Treatment of Multiple Myeloma--Review].

Multiple myeloma (MM) is a hematologic malignancy resulted from genetic mutations in the process of B lymphocyte differentiating into plasma cells, the chemotherapy is the main treatment method, especially with the development of proteasome inhibitors and other drugs, the overall survival rate of MM patients has improved greatly, but the chemoresistance is still an important reason for treatment failure. Chimeric antigen receptor (CAR)-modified T lymphocyte therapy is a new method for tumor adoptive immunotherapy. By means of genetic modification, T cells are able to identify the target antigen specifically, and to kill target cells without major histocompatibility complex (MHC) restriction, therefore the specific killing activity is conspicuous, which has got considerable attention by the public, and has made remarkable achievements particularly in the treatment of B-lineage leukemia and lymphoma, but no systematic literatures were reported in the field of multiple myeloma using CAR therapy. Therefore, this review summarizes the research results of different CAR target in vivo and in vitro experiments for multiple myeloma.

[Dual role of autophagy in chronic myeloid leukemia].

Autophagy is a lysosome-mediated self-degradation process that mediates degradation and recycling of all major components of eukaryotic cells to maintain intracellular homeostasis. Autophagy is associated with leukemo-genesis, treatment, drug-resistance and recurrence of chronic myeloid leukemia (CML). Autophagy is a double-edged sword which has dual characteristics to promote survival and death of CML cells. Thus exploring different roles of autophagy under different conditions, finding out different autophagy pathways and combination with autophagy inducer or inhibitor of autophagy is of great importance to improve therapeutic effect, overcome drug-resistance and recurrence and finally come to a cure. This article makes a summary on the dual role of autophagy in CML.

[Latest advances of research on autophagy and leukemia treatment].

Autophagy, as a conservative self-degradative approach of eukaryotic cells, plays an important role in cellular growth, proliferation,differentiation, death and keeping intracellular steady state. On one hand, autophagy can protect tumor cells to keep survival; on the other hand, autophagy can lead to apoptosis of leukemia cells. The double-edged impacts of autophagy make it to be the hotspot for research on mechanism and treatment of leukemia. This article reviews the diverse effects of autophagy in different leukemia cell lines, as well as its corresponding mechanism resulting in drug resistance, so as to provide theoretic guide for direct rational application of drugs according to their various mechnisms.

Halichondrin B amide acts as tubulin binding agent to exhibit anti-tumor efficacy in hematologic cancers.

Since microtubule dynamics play an indispensable role in cell division, cell motility, cellular transport, cell polarity and cell signalling, the microtubule appears as a highly attractive target for anticancer drug design. The present study demonstrates the role of halichondrin B amide (HCBA), an analog of halichondrin Bas an antitumor agent, its mechanism of action and pharmacokinetics. The results revealed that HCBA effectively inhibitscell growth in a variety of tumor types in vitro. The HCT116 DPC4 (-/-) colon cancer cell line was the most sensitive with an IC50 of 2.02 µM, compared to 3.78 µM in the parental HCT116. It also effectively reduced tumor growth in SCID mice human tumor xenografts of MV-4-11 acute myeloid leukemia, MM.1S multiple myeloma and DU-145 prostate cancer. HCBA caused accumulation of H69S, MM.1S, U266 and 8226/S cells in G2/M-phase after 24 h. There was a significant increase in the positive histone H3 cells from a baseline value of 4.38 to 53.45% in 8226/S cells and from 4.32 to 43.83% in MM.1S cells on treatment with HCBA. The results from pharmacokinetic studies demonstrated relatively high oral bioavailability of 83% with distribution in both plasma and bone marrow. In non-tumor bearing SCID mice injected with a single acute lethal dose of HCBA no myelosuppression was observed. Flow cytometry analysis showed cell cycle arrest in metaphase. It also caused inhibition of tubulin polymerization. Thus, HCBA appears to be a potent agent to arrest cell cyclin the metaphase and inhibit tubulin polymerization. Compared to other existing microtubule destabilizing agents HCBA has good oral bioavailability and lacks MDR cross-resistance acute myelosuppression.

[Mechanisms of Apoptosis Induced by FTY720 in Multiple Myeloma Cell Line U266].

OBJECTIVE: To investigate the effects of FTY720 on apoptosis in multiple myeloma cell line U266 and to clarify the molecular mechanism of apoptosis induced by FTY720. METHODS: U266 cells were treated with 2.5, 5, 10 and 20 µmol/L of FTY720 for 24 hours, the apoptotic rates were tested by flow cytometry with Annexin-V-FITC/PI staining. Then U266 cells were treated with 20 µmol/L FTY720 for 0, 6, 16 and 24 hours, the apoptotic rates were tested. U266 cells were treated with DMSO and FTY720 separately and then were stained with DAPI for 5 min. Drop the cells to the slides and cover the slide with the glass. The cells were observed by fluorescence microscopy. U266 cells were treated with 5 µmol/L FTY720 or together with different doses of Z-VAD-fmk (12.5, 25, 50 µmol/L), a pancaspase inhibitor, for 24 hours, then the cell viability was tested by CCK-8. U266 cells were treated with 2.5, 5, 10 and 20 µmol/L of FTY720 for 24 hours, the expression of cleaved caspase-3 was tested by Western blot. U266 cells were treated with 0, 5, 10 and 20 µmol/L of FTY720 for 24 hours, the expressions of MCL-1, survivin, BCL-2, BID, BAX, BAK, P-ERK were tested by Western blot. RESULTS: The apoptotic rate increased in U266 cells treated with FTY720 and showed the characteristic of time-dependent and dose-dependent manner. Karyopyknosis and nuclearfragmentation could be observed in U266 cells treated with FTY720 after being stained with DAPI under fluorescent microscope. The same effect was not observed in the cells treated with DMSO. Z-VAD-fmk could rescue the apoptosis in U266 cells treated with FTY720 in dose-dependent manner. The expression of MCL-1, survivin and BCL-2 decreased in U266 cells treated with FTY720. The cleavage of BID could be observed in U266 cells treated with FTY720. FTY720 had no effect on the expression of BAX, BAK and P-ERK. CONCLUSION: FTY720 can induce the apoptosis in U266 cells, the apoptosis was Caspase-3-depended. The apoptosis induced by FTY720 is due to the decrease of MCL-1, survivin and BCL-2, which are the inhibitors of apoptosis. Meanwhile, the apoptosis was also due to the activation of BID, which is pro-apoptotic protein.

Standardized fluorescence in situ hybridization testing based on an appropriate panel of probes more effectively identifies common cytogenetic abnormalities in myelodysplastic syndromes than conventional cytogenetic analysis: a multicenter prospective study of 2302 patients in China.

In an attempt to establish the advantages of fluorescence in situ hybridization (FISH) studies over conventional cytogenetic (CC) analysis, a total of 2302 de novo MDS patients from 31 Chinese institutions were prospectively selected in the present study for both CC and standardized FISH analysis for +8, -7/7q-, -5/5q-, 20q- and-Y chromosomal abnormalities. CC analysis was successful in 94.0% of the patients; of these patients, 35.9% of the cases were abnormal. FISH analysis was successful in all 2302 patients and detected at least one type of common cytogenetic abnormality in 42.7% of the cases. The incidences of +8, -7/7q-, -5/5q-, 20q- and-Y chromosomal abnormalities by FISH were 4.1% to 8.7% higher than those by CC. FISH identified abnormalities in 23.6% of the patients exhibiting normal CC results and revealed that 20.7% of the patients with adequate normal metaphases (≥20) had abnormal clones. FISH identified cytogenetic abnormalities in 50.4% of the patients with failed CC analysis. In summary, our multicenter studies emphasised and confirmed the importance of applying standardized FISH testing based on an appropriate panel of probes to detect common cytogenetic abnormalities in Chinese de novo MDS patients, particularly those with normal or failed CC results.

[Effects of TIEG1 on K562 cell apoptosis and expression of BCL-2/BAX, PTEN].

The aim of this study was to investigate the effect of TIEG1 on K562 cell apoptosis and expression of BCL-2/BAX, PTEN. The different concentration(0, 1, 5, 10, 20 ng/ml) of TIEG1 were used to treat K562 cells, the cell growth inhibition rate was detected by using MTT method. After treating K562 cells with 10.00 ng/ml TIEG1, the cell apoptosis was detected with flow cytometry. The RT-PCR was used to detected the expression levels of BCL-2 /BAX and PTEN. The results showed that TIEG1 displays inhibitory effect on proliferation of K562 cells in time-and dose-dependent manner (r = 0.52, P < 0.05) ; after K562 cells were treated for 6, 12, 24 and 48 h, the IC50 of TIEG1 were 48.19, 18.72, 9.5 and 3.85 ng/ml respectively. After treating K562 cells with 10.00 ng/ml TIEG1 for 0, 6, 12, 24, 48 h, the apoptosis rate were (2.13 ± 0.42)%, (7.79 ± 0.71)%, (11.17 ± 1.37)%, (24.66 ± 0.29)% and (48.60 ± 1.38)% respectively, and there was significant difference between groups(P < 0.05). In process of K562 cell apoptosis, the expression level of BCL-2 gradually decreased (r = 0.48, P < 0.05), meanwhile the expression levels of BAX (r = 0.69, P < 0.05) and PTEN (r = 0.57, P < 0.05) gradually increased. It is concluded that TIEG1 can indue apoptosis of K562 cells and inhibit K562 cell proliferation in time-and dose-dependent manner. In apoptosis process of K562 cells induced by TIEG1, the expression changes of BCL-2/BAX and PTEN associate with the K562 cell apoptosis.

[Inducing effects of ursolic acid on Jurkat cell apoptosis and its mechanisms].

The study was aimed to investigate the inducing effect of ursolic acid (UA) on the apoptosis of human T-cell leukemia/lymphoma (Jurkat), and whether the regulation of PTEN involved in the effect of UA on Jurkat cells. The Jurkat cells were treated with different concentrations of UA for different time. The cell proliferation was analyzed with cytotoxicity test (CCK8 method). Cell apoptosis was detected by fluorescence microscopy and flow cytometry. The expression of PTEN mRNA was detected by real-time quantitative PCR. The results indicated that UA could significantly inhibited the viability of Jurkat cells treated with 10-80 µmol/L and in dose- and time-dependent manner. UA could induce Jurkat cell apoptosis in a dose-dependent manner, which was statistical different from the control at the same time (P < 0.05). PTEN mRNA expression was up-regulated by UA, which was statistical different from the control (P < 0.05). It is concluded that UA may induce Jurkat cell apoptosis by up-regulating the PTEN mRNA expression.

Association of ABCB1 polymorphisms with the efficacy of ondansetron in chemotherapy-induced nausea and vomiting.

PURPOSE: Resistance to the antiemetic ondansetron is still a major problem resulting in discomfort and poor compliance with chemotherapy in acute myeloid leukemia (AML) patients. Based on our hypothesis that this clinical resistance to ondansetron is associated with ABCB1 genetic polymorphisms, we investigated whether ABCB1 gene variations affect the efficacy of ondansetron in chemotherapy-induced nausea and vomiting. METHODS: AML patients (n = 215) treated for 3 days with high-dose cytarabine were enrolled in this study. Thirty minutes before the beginning of chemotherapy, 8 mg ondansetron was administered intravenously, followed by 24 mg by continuous infusion and 8 mg intravenously, once per day, until 2 days after chemotherapy. Chemotherapy-induced nausea and vomiting occurrence in the acute and delayed phases was calculated. ABCB1 and CYP2D6 polymorphisms were analyzed by allele-specific matrix-assisted laser desorption. Basic clinical characteristics of the AML patients were collected from medical records. FINDINGS: No differences in genotype distribution frequencies of ABCB1 polymorphisms and haplotypes were observed in patients with different CYP2D6-predicted phenotypes. During the acute phase, patients with the CG haplotype (C3435T and G2677T) were associated with a high risk of grade 3/4 nausea and vomiting (P = 0.003 and P = 0.026, respectively). After adjustment for age, sex, smoking status, alcohol drinking status, body surface area, body mass index, and Eastern Cooperative Oncology Group-Performance Status, multivariate survival analysis implicated the CG haplotype as a predictive marker of the risk of grade 3/4 chemotherapy-induced nausea and vomiting in AML patients (P = 0.003 and P = 0.039, respectively). In addition, a significant association between the 3435CC genotype and grade 3/4 vomiting in AML patients was observed (P = 0.016). However, no association between these ABCB1 gene polymorphisms and ondansetron efficacy was found in the delayed phase. IMPLICATIONS: These findings suggest that ABCB1 gene polymorphisms are associated with antiemetic efficacy of ondansetron in the acute phase after high-dose cytarabine chemotherapy in AML patients.