Posted by rob on November 8, 2005 under Uncategorized | 
Cilloni D, Messa F, Arruga F, Defilippi I, Morotti A, Messa E, Carturan S, Giugliano E, Pautasso M, Bracco E, Rosso V, Sen A, Martinelli G, Baccarani M, Saglio G
Leukemia. 2005 Nov 3;
Imatinib represents at present the most attractive therapy for BCR-ABL positive leukemias, even though a percentage of CML patients develop resistance to this compound. For these resistant patients a therapeutic approach based on a combination of drugs is more likely to be effective. In the last years, constitutive NF-kappaB/Rel activity has been demonstrated in several hematological malignancies. As a result, NFkB/Rel-blocking approaches have been proposed as antineoplastic strategies. Furthermore, the identification of specific kinases within the NF-kappaB activation pathway offers a selective target to address tailored therapies. In the current study, we show that the IKK inhibitor PS1145 is able to inhibit the proliferation of CML cell lines and primary BM cells. Moreover, the addition of Imatinib increases the effects of PS1145 in resistant cell lines and BM cells from resistant patients, with a further increase of apoptosis and inhibition of proliferation and colony growth. Our data provide the rational for a new therapeutic approach, which combines Imatinib and the IKK inhibitor PS1145 in CML resistant patients.Leukemia advance online publication, 3 November 2005; doi:10.1038/sj.leu.2403998.
The NF-kappaB pathway blockade by the IKK inhibitor PS1145 can overcome Imatinib resistance.
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Koh TT, Colby TV, Müller NL
Semin Respir Crit Care Med. 2005 Oct ; 26(5): 514-9
Myeloid leukemias are clonal malignancies characterized by the presence of increased numbers of immature myeloid cells in the marrow and peripheral blood. Pulmonary involvement by myeloid leukemia is relatively uncommon and seen mainly in patients with severe disease. The most common form of pulmonary involvement consists of leukemic infiltration along the lymphatics in the peribronchovascular, septal, and pleural interstitial tissue. Less common manifestations include myeloid sarcoma, leukostasis, leukemic cell lysis pneumopathy, and hyperleukocytic reaction. The radiological manifestations of pulmonary leukemic cell infiltration and leukostasis consist mainly of bilateral thickening of the peribronchovascular interstitium and interlobular septa, a pattern that resembles that of interstitial pulmonary edema. The radiological manifestations of leukemic cell lysis pneumopathy and hyperleukocytic reaction consist of symmetric bilateral areas of consolidation. This manuscript reviews the histological and radiological intrathoracic manifestations of myelogenous leukemias.
Myeloid leukemias and lung involvement.
Posted by rob on November 4, 2005 under Uncategorized |
Liu P, Li J, Han ZC, Lu H, Wang Y, Xu B, Peng Z
Leuk Lymphoma. 2005 Dec ; 46(12): 1761-4
Recent investigations support the idea that angiogenesis is involved in the pathophysiology of hematologic malignancies, including chronic myeloid leukemia (CML). The aim of the present study was to evaluate plasma levels of VEGF and bFGF in a cohort of 51 chronic-phase CML patients at the time of diagnosis, as well as to investigate the effect of imatinib therapy on VEGF amounts in CML patients. Plasma VEGF levels were significantly higher in patients studied as compared with the 20 healthy subjects (pElevated plasma levels of vascular endothelial growth factor is associated with marked splenomegaly in chronic myeloid leukemia.
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Seeliger MA, Young M, Henderson MN, Pellicena P, King DS, Falick AM, Kuriyan J
Protein Sci. 2005 Oct 31;
The Abl and Src tyrosine kinases are key signaling proteins that are of considerable interest as drug targets in cancer and many other diseases. The regulatory mechanisms that control the activity of these proteins are complex, and involve large-scale conformational changes in response to phosphorylation and other modulatory signals. The success of the Abl inhibitor imatinib in the treatment of chronic myelogenous leukemia has shown the potential of kinase inhibitors, but the rise of drug resistance in patients has also shown that drugs with alternative modes of binding to the kinase are needed. The detailed understanding of mechanisms of protein-drug interaction and drug resistance through biophysical methods demands a method for the production of active protein on the milligram scale. We have developed a bacterial expression system for the kinase domains of c-Abl and c-Src, which allows for the quick expression and purification of active wild-type and mutant kinase domains by coexpression with the YopH tyrosine phosphatase. This method makes practical the use of isotopic labeling of c-Abl and c-Src for NMR studies, and is also applicable for constructs containing the SH2 and SH3 domains of the kinases.
High yield bacterial expression of active c-Abl and c-Src tyrosine kinases.
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Sol V, Lamarche F, Enache M, Garcia G, Granet R, Guilloton M, Blais JC, Krausz P
Bioorg Med Chem. 2005 Oct 28;
An efficient five-step synthesis method was developed to obtain tritolylporphyrin and protoporphyrin IX polyamine conjugates. These compounds were composed of either one polyamine unit (spermidine or spermine) covalently tethered to monocarboxyphenyl tritolylporphyrin or two molecules of polyamines borne by protoporphyrin IX. In each compound, an aliphatic spacer arm is linked to the N(4) polyamine position. Photocytotoxicity of these new compounds was evaluated against K562 human chronic myelogenous leukemia cells and compared to Photofrin II((R)); protoporphyrin IX polyamine conjugates exhibited much stronger photocytocicity than Photofrin II((R)) and were shown to readily induce necrosis in treated cells.
Polyamine conjugates of meso-tritolylporphyrin and protoporphyrin IX: Potential agents for photodynamic therapy of cancers.
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Jo WS, Jeong MH, Jin YH, Jang JY, Nam BH, Son SH, Choi SS, Yoo YH, Kang CD, Lee JD, Jeong SJ
Int J Radiat Biol. 2005 Jul ; 81(7): 531-43
Purpose: We previously reported that herbimycin A (HMA) alters the mode of cell death of K562 cells induced by radiation and enhanced their radiosensitivity. In the present study, we explored the apoptosis-inducing activity of HMA and the fundamental mechanism via which it regulates radiation-induced cell death.Materials and methods: Chronic myelogenous leukemia (CML) cell line K562 was used. For X-irradiation and drug treatment, cells were plated at approximately 2 x 10(5) cells/ml. Exponentially growing cells were treated with 10 Gy of X-ray using a 6-MeV X-ray machine at a dose rate of 200 – 300 cGy/min. The cells were treated with 0.25 muM HMA immediately after irradiation and HMA remained for the entire culture period. The modes of cell death were discriminated by morphological changes, analysis of cell cycle, analysis of the mitochondrial events, and the expression of apoptosis-related proteins.Results: Our data demonstrates that radiation induced a significant time-dependent increase of cell death and failed to sustain a prolonged G2 arrest in K562 cells. Radiation-induced cell death caused the accumulation of cyclinB1 and weak nuclear fragmentation, suggesting a mitotic catastrophe. This mitotic catastrophe was dependent upon the mitochondrial permeability transition pore (PTP) opening and was independent of caspase-3. In contrast, K562 cells treated with radiation and HMA had an accelerated cell death and induced a p53-independent apoptosis. This apoptotic pathway was dependent upon an initial hyperpolarization of the mitochondrial inner membrane, following the release of cytochrome c and subsequent caspase-3 activation.Conclusions: Two mechanisms of radiation-induced cell death in K562 cells, mitotic catastrophe and apoptosis, are regulated through distinct pathways, mitochondria and caspase-independent and -dependent, respectively. The findings of this study may provide new insights into improving the efficiency of radiotherapy in CML patients.
Loss of mitochondrial membrane potential and caspase activation enhance apoptosis in irradiated K562 cells treated with herbimycin A.
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Park TH, Kwon HC, Kim HJ, Han JY, Jeong JS, Han HY, Seo C, Kwak JY, Park JI
Exp Mol Med. 2005 Oct 31; 37(5): 507-11
Imatinib mesylate is a selective Bcr/Abl kinase inhibitor and an effective anticancer agent for Bcr/Abl-positive chronic myelogenous leukemia. Most patients in chronic phase maintain durable responses; however, many in blast crisis fail to respond, or relapse quickly. Mutations within the BCR/ABL kinase domain are the most commonly identified mechanism associated with relapse. To overcome the imatinib resistance in CML, many investigators have tried to clarify molecular mechanism for imatinib resistance in cells of patients who failed to respond to imatinib. Our aim was to invesitigate underlying mechanism for imatinib resistance in SR-1 cells, which were derived from a CML patient in blast crisis. We detected the new mutation of BCR/ABL, resulting in premature termination and loss of BCR/ABL fusion protein expression, which might be possible mechanism for the resistance to imatinib in SR-1 cells.
Detection of single nucleotide insertion of BCR/ABL region in imatinib-resistant human myelogenous leukemia SR-1 cells.
Posted by rob on November 2, 2005 under Uncategorized |
Hui CH
Clin Adv Hematol Oncol. 2003 Sep ; 1(9): 538-59
Treatement of chronic myeloid leukemia (CML) patients using imatinib alone is unlikely to be curative. The challenges in the era of imatinib are to prevent the emergence of imatinib resistance and to identify the most effective alternative approaches for patients who lose imatinib responsiveness. This review describes the possible strategies to overcome imatinib resistance in CML patients based on the current understanding of the action of imatinib and mechanisms of its resistance. The useful laboratory tests to study imatinib resistance and a current Australian CML study employing imatinib dose intensification and sequential combination therapy for newly diagnosed patients are also outlined.
Strategies for the treatment of imatinib-resistant chronic myeloid leukemia.
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Nakagawa Y, Furusyo N, Taniai H, Henzan H, Tsuchihashi T, Hayashi J
Intern Med. 2005 Sep ; 44(9): 994-7
A 25-year-old Japanese man was diagnosed with steroid-resistant Adult Still’s Disease (ASD) in August 2000. No evidence of chronic myelogenous leukemia (CML) had been found during admissions in 2000 and 2001. In August 2002, he was diagnosed with CML with a peripheral white blood count of 69,940/mul and positivity for Philadelphia chromosome and BCR/ABL fusion gene on bone marrow aspiration. No case of CML was reported to develop from ASD. Because a diagnosis of ASD is based on the exclusion of other diseases, we must be cognizant of the possibility of the development of concurrent diseases.
HubMed Abstracts
