Targeting GLI1 Suppresses Cell Growth and Enhances Chemosensitivity in CD34+ Enriched Acute Myeloid Leukemia Progenitor Cells.

Background/aims: Resistance of leukemia stem cells (LSCs) to chemotherapy in patients with acute myeloid leukemia (AML) causes relapse of disease. Hedgehog (Hh) signaling plays a critical role in the maintenance and differentiation of cancer stem cells. Yet its role in AML remains controversial.

Apatinib (YN968D1) enhances the efficacy of conventional chemotherapeutical drugs in side population cells and ABCB1-overexpressing leukemia cells.

P-glycoprotein (P-gp, ABCB1) overexpression and enrichment of stem-like cells are linked to poor prognosis in tumor patients. In this study, we investigated the effect of apatinib, an oral multi-targeted tyrosine kinase inhibitor (TKI) on enhancing the efficacy of conventional anticancer drugs in side population (SP) cells and ABCB1-overexpressing leukemia cells in vitro, in vivo and ex vivo. Our results showed that apatinib significantly enhanced the cytotoxicity and cell apoptosis induced by doxorubicin in SP cells sorted from K562 cells.

[Inhibitory effect of apatinib on HL-60 cell proliferation and its mechanism].

Objective: To investigate the effect of apatinib, a small-molecule vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, on the proliferation of human acute myeloid leukemia HL-60 cells and explore the possible mechanism.

Methods: MTT assay was used to assess the cytotoxicity of apatinib in HL-60 cells. The apoptosis and cell cycle changes of the cells in response to apatinib treatment were analyzed by flow cytometry, and Western blotting was used to assay P-Akt and P-Erk1/2 expressions in the cells.

Prognostic value of the multidrug resistance transporter ABCG2 gene polymorphisms in Chinese patients with de novo acute leukaemia.

Background: Functional polymorphisms of the ABCG2 gene may contribute to individual variability in drug response and the prognosis of patients.

Methods: In the present study, the genetic polymorphisms and expression of ABCG2 were analysed in blasts cells obtained from 184 Chinese patients with de novo acute leukaemia to investigate their possible association with clinical outcomes.

Results: A novel synonymous ABCG2-single nucleotide polymorphism (SNP) at exon 16 (13561218 C/T) and five known SNPs at exon 2 (13608835 G/A), exon 5 (13600044 C/A), intron 10 (13576005 C/T), intron 13 (13564503 C/T) and intron 14 (13563578 A/G) were identified with occurrence rates of 1.

Up-regulation of ABCB1/P-glycoprotein by escaping promoter hypermethylation indicates poor prognosis in hematologic malignancy patients with and without bone marrow transplantation.

We investigated the correlation between MDR1 promoter methylation status and MDR1 expression in 228 hematologic malignancies patients and 90 healthy controls. High level of MDR1 mRNA correlated to promoter hypomethylation and strongly associated with poor prognosis indicated by 2-year survival rates, poor CR rate (without BMT) and high relapse rate (with BMT). Furthermore, relative luciferase activity of methylated MDR1 at promoter -50 region was significantly higher than that of the unmethylated.

Sensitization of ABCG2-overexpressing cells to conventional chemotherapeutic agent by sunitinib was associated with inhibiting the function of ABCG2.

Sunitinib is an ATP-competitive multi-targeted tyrosine kinase inhibitor. In this study, we evaluated the possible interaction of sunitinib with P-glycoprotein (P-gp, ABCB1), multidrug resistance protein 1 (MRP1, ABCC1), breast cancer resistance protein (BCRP, ABCG2) and lung-resistance protein (LRP) in vitro. Our results showed that sunitinib completely reverse drug resistance mediated by ABCG2 at a non-toxic concentration of 2.

[The clinical features, chemotherapy responses and survival of 223 patients with newly diagnosed multiple myeloma].

Objective: To explore the proportion, clinical and laboratory features, chemotherapy responses and long term survival of different kinds of newly diagnosed multiple myeloma (MM) in China.

Methods: The clinical data of 223 cases of newly diagnosed MM patients were gathered in the First Affiliated Hospital of Sun Yat-sen University from Jan, 2000 to Seb, 2007 were retrospectively analyzed.

Results: The proportions of each kind of MM including IgG, IgA, light chain, IgD, IgM and biclonal MM were 48.

[Efficacy of bortezomib combined dexamethasone in 24 patients with multiple myeloma].

Background & Objective: Bortezomib, a potent and reversible proteasome inhibitor, induces apoptosis of myeloma cells, resulting in durable responses in patients with multiple myeloma (MM). This study was to explore the medical effects and side effects of bortezomib combined dexamethasone in treating newly diagnosed and relapsed or refractory MM, and evaluate the safety of this regimen in the patients with renal impairment.

Methods: Twenty-four MM patients were treated with bortezomib and dexamethasone in a 21-day cycle.

[Establishment of an animal model of oral mucositis induced by conditioning regimen of haematopoietic stem cell transplantation].

Objective: To establish a rat model of oral mucositis (OM) induced by busulfan and cyclophosphamide (BUCY) conditioning regimen of hematopoietic stem cell transplantation (HSCT).

Methods: In the model group, busulfan (6.0 mg.

[Efficacy and toxicity of intravenous busulfan-based conditioning before allogeneic peripheral blood stem cell transplantation for leukemia].

Background & Objective: Busulfan (Bu) is commonly used as a component of conditioning regimens for hematopoietic stem cell transplantation. Erratic gastrointestinal absorption as a result of oral administration of Bu not only affects the efficacy, but also increases the risk of toxicity. This study was to analyze the efficacy and toxicity of intravenous Bu and cyclophosphamide (Cy) conditioning before allogeneic peripheral blood stem cell transplantation (allo-PBSCT) for leukemia.

[Effects and prognostic factors of HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia].

Objective: To retrospectively analyze the curative effects and prognostic factors of HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic myelogenous leukemia patients (CML).

Methods: Of the 35 CML patients, 26 were males and 9 were females, with a median age of 32 (12 - 50) years. 30 patients were in chronic phase of CML, 5 patients were in accelerated phase.

[Preliminary report of fludarabine, mitoxantrone and dexamethasone in treating refractory or relapsed multiple myeloma].

Background & Objective: Multiple myeloma has low complete remission rate and high recurrence rate. Recurrence or relapse of the disease is almost inevitable for most of the patients after several cycles of combined chemotherapy. This study was designed to compare efficacy of fludarabine-based regimen (fludarabine, mitoxantrone and dexamethasone) with that of pirarubicin, vincristine and dexamethasone (VAD) on refractory or relapsed multiple myeloma, and analyze their toxicities.

[Study of TRAIL receptors expression on the mononuclear cells from multiple myeloma patients and KM3 cells].

Objective: To study the differential expression of four TRAIL receptors on bone marrow mononuclear cells (BMMNC) from multiple myeloma (MM) patients and myeloma cell line KM3 cells, to compare their altered expressions after chemotherapy and to explore the mechanisms by which TRAIL selectively kills tumor cells.

Methods: Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry were used to investigate the expression of four TRAIL receptors on BMMNCs in 23 MM patients, KM3 cells and 15 controls, and the changes of their expression pattern after chemotherapy and after incubation of KM3 cells with sub-clinical concentration of doxorubicin.

Results: DR4 and DR5 were highly expressed on KM3 cells with no expression of DcR1 and DcR2.

[Efficacy of imatinib mesylate, a specific inhibitor of BCR/ABL tyrosine kinase, on chronic myeloid leukemia in blast phase].

Background & Objective: Chronic myeloid leukemia (CML) in blast phase is refractory with a poor prognosis. This study was to evaluate efficacy of imatinib mesylate, a specific inhibitor of BCR/ABL tyrosine kinase, on CML in blast phase.

Methods: Nineteen patients with CML in blast phase (imatinib treatment group) received induction of cytarabine-based standard chemotherapy for 2 cycles, and 400 mg/d of imatinib mesylate for 4 weeks.

[Expression of CD117 antigen on multiple myeloma and its significance].

Background & Objective: Leukocyte differentiation antigen CD117 is one of the targets that tyrosine kinase selective inhibitors work on. Whether CD117 is expressed on the cell surface, and the expression level are highly correlated with tyrosine kinase selective inhibitors. This study was designed to investigate the expression of CD117 on multiple myeloma (MM) cells, which may provide a theoretical evidence for the use of tyrosine kinase selective inhibitors in MM,meanwhile,the importance of CD117 expression on MM cells was estimated.

[Effects of combination therapy with all-trans retinoic acid and arsenic trioxide on acute promyelocytic leukemia].

Background & Objective: The mechanism of effect of arsenic trioxide on promyelocytic leukemia is different from that of all-trans retinoic acid. Arsenic trioxide exerts its action by accelerating cell apoptosis, while all-trans retinoic acid by inducing cell differentiation. However, both drugs can inhibit the transcription of tissue factor (TF) mRNA in acute promyelocytic leukemia, and decrease TF level and coagulative activity to normalize coagulopathy.

[Comparison of two conditioning regimens in treatment of leukemia by allogeneic hematopoietic stem cell transplantation].

Background & Objective: The conditioning regimens are the critical factors in the allogeneic hematopoietic stem cell transplantation. This study was conducted to compare the effectiveness and side-effects of two conditioning regimens in allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Methods: Twenty-one cases received busulfan(BU) 16 mg/kg plus cyclophosphamide(CY) 120 mg/kg,the other 23 cases received total body irradiation(TBI) 7.