Posted by rob on November 13, 2005 under Uncategorized | 
Scherr M, Chaturvedi A, Battmer K, Dallmann I, Schultheis B, Ganser A, Eder M
Blood. 2005 Nov 8;
Although targeting the BCR-ABL tyrosine kinase activity by imatinib mesylate (STI571) has rapidly become first line therapy in chronic myeloid leukemia (CML), drug resistance suggests that combination therapy directed to a complementing target may significantly improve treatment results. To identify such potential targets, we used lentivirus-mediated RNA interference (RNAi) as a tool for functional genomics in cell lines as well as primary normal and CML CD34+ cells. In a conditional cell culture model, we demonstrate that RNAi mediated reduction of SHP2, STAT5, and Gab2 protein expression inhibits Bcr-Abl- but not cytokine-dependent proliferation in a dose dependent manner. Similarily, colony formation of purified primary CML- but not of normal CD34+ colony-forming cells is specifically reduced by inhibition of SHP2, STAT5, and Gab2 expression, respectively. In addition, coexpression of both anti-Bcr-Abl and anti-SHP2 shRNAs from a single lentiviral vector induces stronger inhibition of colony formation as compared to either shRNA alone. The data indicate that Bcr-Abl expression may affect the function of normal signaling molecules. Targeting these molecules may harbour significant therapeutic potential for the treatment of CML.
Enhanced sensitivity to inhibition of SHP2, STAT5, and Gab2 expression in chronic myeloid leukemia (CML).
Posted by rob on under Uncategorized |
Bocchia M, Abruzzese E, Forconi F, Ippoliti M, Trawinska MM, Pirrotta MT, Raspadori D, Tozzi M, Gozzetti A, Lauria F
Leukemia. 2005 Nov 10;
No abstract yet.
Imatinib does not impair specific antitumor T-cell immunity in patients with chronic myeloid leukemia.
Posted by rob on under Uncategorized |
Roy L, Guilhot J, Martineau G, Guilhot F
Leukemia. 2005 Nov 10;
No abstract yet
HubMed Abstracts
Posted by rob on under Uncategorized |
Stanojkovic TP, Zizak Z, Mihailovic-Stanojevic N, Petrovic T, Juranic Z
J Exp Clin Cancer Res. 2005 Sep ; 24(3): 387-95
The present work examines the effects of beta and alpha1-adrenoceptor antagonist carvedilol, and angiotensin converting enzyme (ACE) inhibitor captopril, on in vitro growth of tumor cell lines derived from breast tumor (MDA-MB-361), melanoma (Fem-x), cervix adenocarcinoma (HeLa) and human myelogenous leukemia (K562). Carvedilol or captopril were applied on malignant cells at 0.1, 1, 5, 10 and 50 micromol. Cell survival was determined 48 hrs after drugs action by MTT. On all cell lines tested, carvedilol was a very potent inhibitor of cell proliferation. The order of sensitivity of various human cell lines to carvedilol’s antiproliferative action was: myelogenous leukemia K562 (IC50 = 22.66 +/- 2.14 micromol), > cervix carcinoma HeLa (IC50 = 30.56 +/- 5.16 micromol), > melanoma Fem-x (IC50 = 32.17 +/- 5.75 micromol), > breast tumor MDA-MB-361 (IC50 = 35.04 +/- 2.95 micromol). In contrast, captopril, used in doses from 0.1-50 micromol, was ineffective (IC50 > 50 micromol) to the same cell lines. It is important to note that captopril in concentrations > 1 micromol led to a statistically significant increase in the percent of survived melanoma Fem-x cells (p Inhibition of proliferation on some neoplastic cell lines-act of carvedilol and captopril.
Posted by rob on under Uncategorized |
Li Y, Yang L, Chen S, Zhang Y, Wu X
Hematology. 2005 Oct ; 10(5): 387-92
Understanding the clonality and restricted usage of the TCR Vbeta repertoire of expanded T-cells induced by the chronic myelogenous leukemia (CML) associated antigen may be useful in helping design new immunotherapeutic strategies specifically for CML. T-cells from cord blood that had been stimulated by different stimulators (IL-2, PHA, CML cells, K562 cells and bcr-abl peptide) were amplified in vitro by liquid T-cell culture and the mixed lymphocyte and tumor cell culture (MLTC) method. By using the RT-PCR, the CDR3 segments of 24 variable region genes of TCR beta was analyzed in T-cells from 22 cases of cord blood before and after T-cell culture, to observe the usage of TCR Vbeta repertoire. The PCR products were further labeled with fluorescence and analyzed by the Genescan technique for the CDR3 size, to evaluating clonality of the detectable TCR Vbeta T-cells. Only a part of 24 Vbeta subfamily T-cells (3-15 subfamilies) could be detected, however, all of the 24 TCR Vbeta subfamily of T-cells were detected after in vitro culture with PHA or IL-2+anti-CD3 antibody. The number of expressed TCR Vbeta subfamilies was gradually reduced by prolonging the time of culture with CML-associated antigens. The restricted expression of TCR Vbeta subfamilies and oligoclonal expansion of Vbeta21 T-cells were found in cultured T-cells induced by CML cells, K562 cells or bcr-abl peptide. In conclusion, T-cells from cord blood may have the potential capability of proliferation in different TCR Vbeta subfamily T-cells, and the ability for restricted expression and clonal expansion, when T-cells were induced by CML associated antigen.
The TCR Vbeta repertoire usage of T-cells from cord blood induced by chronic myelogenous leukemia associated antigen.
Posted by rob on under Uncategorized |
Rosato RR, Almenara JA, Maggio SC, Atadja P, Craig R, Vrana J, Dent P, Grant S
Mol Cancer Ther. 2005 Nov ; 4(11): 1772-85
Interactions between the novel histone deacetylase inhibitor LAQ824 and the cyclin-dependent kinase inhibitor roscovitine were examined in human leukemia cells. Pretreatment (24 hours) with a subtoxic concentration of LAQ824 (30 nmol/L) followed by a minimally toxic concentration of roscovitine (10 mumol/L; 24 hours) resulted in greater than additive effects on apoptosis in U937, Jurkat, and HL-60 human leukemia cells and blasts from three patients with acute myelogenous leukemia. These events were associated with enhanced conformational changes in Bax; mitochondrial release of cytochrome c, Smac/DIABLO, and apoptosis-inducing factor; and a marked increase in caspase activation. LAQ824/roscovitine-treated cells displayed caspase-dependent down-regulation of p21(CIP1) and Mcl-1 and a pronounced caspase-independent reduction in X-linked inhibitor of apoptosis (XIAP) expression. The lethality of this regimen was significantly attenuated by ectopic expression of XIAP, a nuclear localization signal-defective p21(CIP1) mutant, Mcl-1, and Bcl-2. Combined exposure to LAQ824 and roscovitine resulted in a significant reduction in XIAP mRNA levels and diminished phosphorylation of the carboxyl-terminal domain of RNA polymerase II. Notably, roscovitine blocked LAQ824-mediated differentiation. Finally, LAQ824 and roscovitine individually and in combination triggered an increase in generation of reactive oxygen species; moreover, coadministration of the free radical scavenger N-acetylcysteine prevented LAQ824/roscovitine-mediated mitochondrial injury and apoptosis. Collectively, these findings suggest that combined treatment of human leukemia cells with LAQ824 and roscovitine disrupts maturation and synergistically induces apoptosis, lending further support for an antileukemic strategy combining novel histone deacetylase and cyclin-dependent kinase inhibitors.
Potentiation of the lethality of the histone deacetylase inhibitor LAQ824 by the cyclin-dependent kinase inhibitor roscovitine in human leukemia cells.
Posted by rob on under Uncategorized |
Kantarjian H
J Natl Compr Canc Netw. 2005 Nov ; 3 Suppl 1: S41-5
No abstract yet
Trends in the management of chronic myelogenous leukemia.
Posted by rob on under Uncategorized |
Ye QD, Gu LJ, Zhao YX, Zhao JC, Chen WG, Zhang B, Jiang LM
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2005 Oct ; 13(5): 759-63
To explore the effects of tetra-arsenic tetra-sulfide (As(4)S(4)) in treatment of human chronic myelogenous leukemia K562 cells and its mechanism, trypan blue staining and microculture MTS assay were used to measure the effects of As(4)S(4) on growth inhibition of K562 cells; the morphologic change was determined by Wright’s staining assay. The apoptosis rate and cell cycle were detected by flow cytometry; the changes of transcript and protein level were determined by real-time quantitative RT-PCR and Western blot analysis, respectively. The results indicated that As(4)S(4) had signigicant cytotoxicity on K562 cells. At the concentration of 0.5 micromol/L, the cell viability decreased significantly after being cultured with As(4)S(4) for 24 hours. When the concentration was lower than 0.1 micromol/L, As(4)S(4) had a little effect on K562 cells. The effect of As(4)S(4) on K562 was time- and concentration- dependent. After being cultured with As(4)S(4) at the concentration of 1.0 micromol/L for 24 to 48 hours, K562 cells displayed typical morphological changes of apoptosis. At a concentration greater than or equal to 1.0 micromol/L, As(4)S(4) could induce apoptosis significantly. After 12 hours of incubation with 1.0 micromol/L As(4)S(4), the apoptosis rate increased from (3.47 +/- 0.42)% to (6.16 +/- 0.98%). At the same time, the percentage of cells in G(1) phase decreased from (69.65 +/- 3.24)% to (50.53 +/- 2.86)%, whereas the percentage of cells in G(2)/M phase increased from (9.56 +/- 2.51)% to (12.91 +/- 2.13)%. The mRNA level of Bcl-X(L) and the protein level of pAkt were down-regulated after the inhibition of As(4)S(4), while the mRNA expression of Bcl-2, Bad and Bax had no change. Both of the transcript and protein level of bcr-abl had no change after incubation with As(4)S(4). It is concluded that As(4)S(4) can inhibit the growth of K562 cells efficiently through inducing apoptosis and cell cycle arrest. It seems that As(4)S(4) interferes with pAkt pathway and down-regulates Bcl-X(L), which may be involved in the response of K562 to this agent.
[Apoptosis Mechanism in Human Chronic Myelogenous Leukemia K562 Cells Induced by Tetra-arsenic Tetra-sulfide.]
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