Posted by rob on April 28, 2010 under Uncategorized | 
Liquid crystal-related compound-induced cell growth suppression and apoptosis in the chronic myelogenous leukemia K562 cell line.
Invest New Drugs. 2010 Apr 27;
Authors: Fukushi Y, Hazawa M, Takahashi K, Yoshizawa A, Kashiwakura I
Liquid crystals are the state of matter existing between the liquid and the crystalline phase, and there is a recent surging interest in its biological effects. Our previous study showed that liquid crystal-related compounds (LCRCs), which are precursors of the liquid crystal, enhanced hematopoietic differentiation at a relatively low concentration (Biol Pharm Bull, 32, 2009). However, biological potentials of LCRCs on tumor cells are unclear. In this study, the biological activity of 16 LCRCs to a chronic myelogenous leukemia cell line, K562, was evaluated. As a result, two compounds, 2-(4-butoxyphenyl)-5-(4-hydroxyphenyl)pyrimidine (compound 7) and 2-{4-(4-hexyloxyphenyl)phenyl}-5-hydroxypyrimidine (compound 9) showed marked growth suppression of K562 cells at muM range. These compounds are similar in structure with a core of three aromatic rings including a pyrimidine ring and residues of one alkyl chain and one hydroxide on either side. In addition, only compound 7 induced the activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, and apoptosis of K562 cells. The contrasting results between compounds 7 and 9 indicate different mechanisms to suppress the cell proliferation between the two compounds. These results suggest the possibility of LCRCs for application as new antitumor drugs.
PMID: 20422253 [PubMed - as supplied by publisher]
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Tautomerization of 2-nitroso-N-arylanilines by coordination as N,N’-chelate ligands to rhenium(i) complexes and the anticancer activity of newly synthesized oximine rhenium(i) complexes against human melanoma and leukemia cells in vitro.
J Inorg Biochem. 2010 Apr 1;
Authors: Wirth S, Wallek AU, Zernickel A, Feil F, Sztiller-Sikorska M, Lesiak-Mieczkowska K, Bräuchle C, Lorenz IP, Czyz M
The synthesis, structural characterization and biological activity of eight ortho-quinone(N-aryl)-oximine rhenium(i) complexes are described. The reaction of the halogenido complexes (CO)(5)ReX (X=Cl (4), Br (5)) with 2-nitroso-N-arylanilines {(C(6)H(3)ClNO)NH(C(6)H(4)R)} (R=p-Cl, p-Me, o-Cl, H) (3a-d) in tetrahydrofurane (THF) yields the complexes fac-(CO)(3)XRe{(C(6)H(3)ClNO)NH(C(6)H(4)R)} (6a-d, 7a-d) with the tautomerized ligand acting as a N,N’-chelate. The substitution of two carbonyl ligands leads to the formation of a nearly planar 5-membered metallacycle. During coordination the amino-proton is shifted to the oxygen of the nitroso group which can be observed in solution for 6 and 7 by (1)H NMR spectroscopy and in solid state by crystal structure analysis. After purification, all compounds have been fully characterized by their (1)H and (13)C NMR, IR, UV/visible (UV/Vis) and mass spectra. The X-ray structure analyses revealed a distorted octahedral coordination of the CO, X and N,N’-chelating ligands for all Re(i) complexes. Biological activity of four oximine rhenium(i) complexes was assessed in vitro in two highly aggressive cancer cell lines: human metastatic melanoma A375 and human chronic myelogenous leukemia K562. Chlorido complexes (6a and 6c) were more efficient than bromido compounds (7d and 7b) in inducing apoptotic cell death of both types of cancer cells. Melanoma cells were more susceptible to tested rhenium(i) complexes than leukemia cells. None of the ligands (3a-d) showed any significant anticancer activity.
PMID: 20421133 [PubMed - as supplied by publisher]
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Hydroxylation of diosgenin by Absidia coerulea.
Nat Prod Commun. 2010 Mar;5(3):373-6
Authors: Zhao Y, Sun LM, Wang XN, Shen T, Ji M, Lou HX
Microbial transformation of diosgenin (1) using Absidia coerulea yielded five new polar metabolites, which were identified as (25R)-spirost-5-en-3 beta,7 beta,12 beta,25 alpha-tetrol (2), (25S)-spirost-5-en-3 beta,7 alpha,12 beta,25 beta-tetrol (3), (25S)-spirost-5-en-3 beta,7 beta,12 beta,25 beta-tetrol (4), (25R)-spirost-5-en-3 beta,7 alpha,12 beta,25 alpha-tetrol (5), and (25R)-spirost-5-en-3 beta,7 beta,12 beta,24 beta-tetrol (6). Their structures were established on the basis of mass spectrometry and multi-dimensional NMR spectroscopy. The characteristic transformations observed were C-7 alpha, C-7 beta, C-12 beta, C-24 beta, C-25 alpha, and C-25 beta hydroxylation. The cytotoxicity of compounds 1-6 was evaluated against the human myelogenous leukemia K562 cell line and squamous cell carcinoma KB parental cell lines. Compounds 2-6 exhibited weak cytotoxicity against K562 and KB cells and were less potent than the parent compound 1.
PMID: 20420310 [PubMed - in process]
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[Evaluation of the efficacy of liposomal amphotericin B]
Kansenshogaku Zasshi. 2010 Mar;84(2):182-6
Authors: Iyama S, Murase K, Sato T, Kikuchi S, Sato Y, Kobune M, Takimoto R, Kato J
A retrospective study was performed to evaluate the efficacy and safety of liposomal amphotericin B (L-AMB) in a total of 32 cases who were among patients hospitalized at the Fourth Department of Internal Medicine, Sapooro Medical University from December 2006 to April 2008. Primary diagnoses were hematologic diseases in 87.5% of subjects. The most common hematologic diseases included acute myelogenous leukemia in 50% of the subjects, followed by malignant lymphoma in 12.5% of the subjects. The mean administration period was 14.2 +/- 12.9 days, and the mean cumulative dose was 1,786 +/- 2,181 mg. L-AMB improved 21 of 29 cases (72.4%) with some fungal infections or fever-associated neutropenia. Adverse events occurred in 9 cases to a slight degree, in 7 cases to a moderate degree, and in no case to a severe degree. Hypokalemia and hypercreatininemia were seen in 7 cases (21.9%) and 4 cases (12.5%), respectively, but these adverse reactions were so mild that the treatment did not need to be discontinued. Any adverse reactions for which treatment administration was discontinued were confirmed to have disappeared at the end of the study. These results support the efficacy and safety of L-AMB in accordance with previous foreign reports. It was noteworthy that early use of L-AMB prior to established diagnosis sometimes better therapeutic outcomes. It was also suggested that L-AMB could be safely administered while controlling electrolyte balance, such as serum potassium concentration, with sufficient fluid replacement, including physiological saline infusion. There are limitations in the use of the conventional form of amphotericin B because of its renal toxicity and other reasons. However, L-AMB had fewer side effects, so the agent was considered useful for the treatment of hematologic disease patients who either had mycosis or carried a risk for fungal infection.
PMID: 20420163 [PubMed - in process]
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Hypothesis: upfront use of ABL kinase inhibitor combination, either simultaneously or sequentially, in high-risk Ph+ leukemias?
Ann Hematol. 2010 Jun;89(6):531-3
Authors: Carella AM
A sequential treatment approach is the rule in CML and Ph(+) ALL with imatinib failure being followed by second-line tyrosine kinase inhibitors. The sequential strategy may be vulnerable to compound mutations. An alternative and fascinating hypothesis discussed in this paper is the upfront use, at least in very high-risk Ph(+) leukemias, of ABL kinase inhibitor combinations, either simultaneously or sequentially to target a wider range of mutations-based drug resistance. The main questions are: will TKI cocktails be able to eliminate the leukemic compartment? Which are the correct doses? Which are the long-term effects? Clinical trials have been recently initiated, and the future will give us the answer to all these questions.
PMID: 20165848 [PubMed - indexed for MEDLINE]
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Bilateral toxoplasma retinochoroiditis in a patient with chronic myeloid leukemia treated with imatinib mesylate.
Ocul Immunol Inflamm. 2010 Jan;18(1):64-5
Authors: Basu S, Das T, Biswas G
A 48-year-old man, on imatinib therapy for chronic myeloid leukemia, developed bilateral retino-choroiditis. Visual acuity was 20/100 and counting fingers at 2 m in both the right and left eye. Vitreous biopsy (left eye) revealed Toxoplasma gondii genome by polymerase chain reaction. Serum anti-toxoplasma IgG levels were significantly elevated. Blood counts were normal. Bcr-Abl/Abl transcript ratio was 0.016%. He was treated with oral co-trimoxazole, to which corticosteroids in tapering doses were added later. Imatinib therapy was continued. After 6 weeks of therapy, all retinal lesions regressed and vision improved to 20/30 and 20/40 in right and left eyes, respectively.
PMID: 20128654 [PubMed - indexed for MEDLINE]
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Molecular pathogenesis of tyrosine kinase resistance in chronic myeloid leukemia.
Curr Opin Hematol. 2010 Mar;17(2):91-6
Authors: La Rosée P, Hochhaus A
PURPOSE OF REVIEW: The molecular pathogenesis of resistance against tyrosine kinase inhibitors imatinib, nilotinib, or dasatinib in patients treated for chronic myeloid leukemia is best understood based on mutations within the ABL-kinase domain. However, in about 50% of patients, clinical resistance so far cannot be linked to known mutations. Mutation-independent resistance development is imparted by a multifactorial array of mechanisms. The purpose of this review is to summarize recent publications on molecular mechanisms that govern the development of clinical resistance. Studies on the second-line inhibitors dasatinib and nilotinib addressing clinical efficacy in the presence of preexisting kinase mutations have largely confirmed the in-vitro prediction. With regard to mutation-independent resistance, new insights into the multifactorial resistance regulation were gained. Preclinical and clinical findings have revitalized the interest in interferon-alpha as a potentially useful adjunct for tyrosine kinase inhibitor-based treatment. The dogma of continuous kinase inhibition necessary for optimal efficacy has been challenged by clinical and preclinical data. SUMMARY: Elucidation of the complexity of resistance development most likely will help to preempt evolution of resistant disease. Clinical studies now focus on dose modifications, drug scheduling, optimized inhibitors, and drug combinations aiming to prevent resistance development.
PMID: 20071983 [PubMed - indexed for MEDLINE]
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Managing imatinib resistance in chronic myeloid leukaemia.
Curr Opin Hematol. 2010 Mar;17(2):97-103
Authors: Osborn M, Hughes T
PURPOSE OF REVIEW: Imatinib mesylate has proven to be an extremely effective and generally well tolerated drug, producing durable responses in most patients with chronic phase chronic myeloid leukaemia. Nonetheless, a minority of patients are resistant or intolerant to imatinib; proposed alternative strategies include imatinib dose escalation, switching to a second-generation tyrosine kinase inhibitor or, in rare instances, allogeneic stem cell transplantation. The aim of this review is to aid clinicians in the recognition, investigation and appropriate treatment of imatinib resistance. RECENT FINDINGS: Although response definitions are still being refined, there is emerging evidence that earlier intervention with next-line therapy is associated with better outcomes, reinforcing the importance of careful monitoring in all patients and mutation analysis in those losing response. Imatinib dose escalation can produce sustained responses in patients resistant to standard dosing, but is frequently poorly tolerated. Dasatinib and nilotinib are both effective next-line therapies, with clinical studies confirming a small number of BCR-ABL kinase domain mutations that confer insensitivity to one or both of these agents. SUMMARY: The development of imatinib resistance, as defined by the revised European LeukemiaNet criteria, should trigger a careful review of drug adherence or recent interruptions, a repeat bone marrow aspirate and mutation analysis. In the absence of clinically relevant mutations, the choice between dasatinib and nilotinib should be guided by the potential adverse effects specific to each drug and relevant comorbidities.
PMID: 20061946 [PubMed - indexed for MEDLINE]
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[Expression of hOCT1 in patients with chronic myelogeneous leukemia treated by imatinib mesylate]
Sichuan Da Xue Xue Bao Yi Xue Ban. 2009 Sep;40(5):893-6
Authors: Zheng CX, Zhu HL, Liu HW, Hu N, Meng WT
OBJECTIVE: To measure the expression of hOCT1 gene in patients with Chronic Myelogeneous Leukemia (CML) and to explore its role in the progress of the disease and responding to Imatinib Mesylate (IM) treatment. METHODS: Sixty three peripheral blood or bone marrow samples were taken from 30 patients with CML (20 in chronic phase, 10 in advanced phase). The samples were divided into two groups: responding (optimal and suboptimal) and non-responding according to effectiveness of the IM treatment. The mRNA levels of hOCT1 gene were detected with RT-PCR (SQ-PCR), 3, 6, 9, 12 and 15 months after the IM therapy. The associations between hOCT1 gene levels and clinical presentations, laboratory indicators and cytogenetic findings were analysed. RESULTS: No significant difference in the expression levels of hOCT1 gene was found before and after the IM treatment (0.5110+/-0.1629 vs 0.5207+/-0.1909, P=0.5840). No significant difference in the expression levels of hOCT1 genes was found between the patients in chronic phase and the patients in advanced phase before the IM treatment (0.5525+/-0.1985 vs 0.4490+/-0.1717, P=0.1090). The levels of hOCT1 did not have significant changes 3, 6, 9, 12 and 15 months after the IM treatment (P=0.3412). No significant difference in the expression levels of hOCT1 genes was found between the 15 patients with optimal and suboptimal responding to IM and the 5 patients with no responding to IM (0.5820+/-0.1460 vs 0.4640+/-0.1781, P=0.127). Although the hOCT1 levels of the 16 chronic patients increased after IM treatment compared to the baseline (0.5207+/-0.1909 vs 0.5110+/-0.1629, P=0.001), there was no significant correlation between the increase of hOCT1 and the decrease of BCR-ABL (P=0.821). CONCLUSION: hOCT1 has no association with the stage and course of CML, nor with the effectiveness of IM therapy.
PMID: 19950608 [PubMed - indexed for MEDLINE]
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Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template.
Chem Biol Drug Des. 2010 Jan;75(1):18-28
Authors: Zhou T, Commodore L, Huang WS, Wang Y, Sawyer TK, Shakespeare WC, Clackson T, Zhu X, Dalgarno DC
Bcr-Abl is the oncogenic protein tyrosine kinase responsible for chronic myeloid leukemia (CML). Treatment of the disease with imatinib (Gleevec) often results in drug resistance via kinase mutations at the advanced phases of the disease, which has necessitated the development of new mutation-resistant inhibitors, notably against the T315I gatekeeper mutation. As part of our efforts to discover such mutation resistant Abl inhibitors, we have focused on optimizing purine template kinase inhibitors, leading to the discovery of potent DFG-in and DFG-out series of Abl inhibitors that are also potent Src inhibitors. Here we present crystal structures of Abl bound by two such inhibitors, based on a common N9-arenyl purine, and that represent both DFG-in and -out binding modes. In each structure the purine template is bound deeply in the adenine pocket and the novel vinyl linker forms a non-classical hydrogen bond to the gatekeeper residue, Thr315. Specific template substitutions promote either a DFG-in or -out binding mode, with the kinase binding site adjusting to optimize molecular recognition. Bcr-Abl T315I mutant kinase is resistant to all currently marketed Abl inhibitors, and is the focus of intense drug discovery efforts. Notably, our DFG-out inhibitor, AP24163, exhibits modest activity against this mutant, illustrating that this kinase mutant can be inhibited by DFG-out class inhibitors. Furthermore our DFG-out inhibitor exhibits dual Src-Abl activity, absent from the prototypical DFG-out inhibitor, imatinib as well as its analog, nilotinib. The data presented here provides structural guidance for the further design of novel potent DFG-out class inhibitors against Src, Abl and Abl T315I mutant kinases.
PMID: 19895503 [PubMed - indexed for MEDLINE]
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Plasmablastic crisis of Philadelphia chromosome-positive chronic myeloid leukemia.
Ann Hematol. 2010 Jun;89(6):641-2
Authors: Manola KN, Pantelidou D, Papaioannou M
PMID: 19844710 [PubMed - indexed for MEDLINE]
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[Bone marrow morphologic features in patients treated with imatinib for Philadelphia chromosome positive chronic myeloid leukemia]
Zhonghua Xue Ye Xue Za Zhi. 2004 Mar;25(3):158-62
Authors: Jiang Q, Chen SS, Jiang B, Jiang H, Shi HL, Lu Y, Lu DP
OBJECTIVES: To assess bone marrow morphologic changes in Philadelphia-chromosome positive chronic myeloid leukemia (Ph(+)-CML) patients treated with Imatinib, and to evaluate the correlation of the morphologic changes with hematological or cytogenetic responses. METHODS: One hundred and seventeen patients with Ph(+) CML: 54 in chronic phase but failed to interferon-alpha treatment, 41 in accelerated phase, 22 in blastic phase received oral administration of Imatinib 400 or 600 mg once daily for more than 18 months. RESULTS: All of the patients responded to the treatment, including complete hematological response, bone marrow response and return to chronic phase, bone marrow cellularity and myeloblast count reduced significantly to non-CML picture. Myeloid/erythroid ratio and megkaryocyte count were decreased significantly in most patients in chronic and accelerated phases (P < 0.05). Bone marrow hypoplasia or aplasia was associated with lower cytogenetic response rates in patients in chronic phase (58.8% vs 86.5%, P = 0.035), lower complete hematological response in patients in accelerated phase (26.3% vs 75.0%, P = 0.004), and 6-month overall survival in patients in blastic phase (77.8% vs 16.7%, P = 0.009). Patients in advanced stage obtained non-CML marrow picture in 1 month of treatment had better prognosis. 18-month disease progression rates were lower (25% vs 75%, P = 0.028) and overall survival rates higher (75.0% vs 11.8%, P = 0.004) in patients obtained non-CML picture marrows than in those with CML marrows picture in accelerated phase. Hematological response rate and overall survival of more than 6 months were higher in patients with non-CML marrows picture than those with CML marrows picture (100.0% vs 40.0%, P = 0.017 and 83.3% vs 26.7%, P = 0.046 respectively) in blastic phase. CONCLUSIONS: Normal marrow appearance can be sustained under continuous treatment of Imatinib in CML patients who achieved hematological responses.
PMID: 15182585 [PubMed - indexed for MEDLINE]
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In this study, the biological activity of 16 LCRCs to a chronic myelogenous leukemia cell line, K562, was evaluated. As a result, two compounds, 2-(4-butoxyphenyl)-5-(4-hydroxyphenyl)pyrimidine (compound 7) and 2-{4-(4-hexyloxyphenyl)phenyl}-5-hydroxypyrimidine (compound 9) showed marked growth suppression of K562 cells at muM range. These compounds are similar in structure with a core of three aromatic rings including a pyrimidine ring and residues of one alkyl chain and one hydroxide on either side. In addition, only compound 7 induced the activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, and apoptosis of K562 cells. The contrasting results between compounds 7 and 9 indicate different mechanisms to suppress the cell proliferation between the two compounds. T…
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Abstract: Imatinib mesylate is used with increasing frequency and duration for the treatment of chronic myelogenous leukemia (CML), gastrointestinal stromal tumor (GIST), and other neoplastic conditions. Although muscular complaints are common, elevations of creatine kinase (CK) are listed as (Source: Leukemia Research)
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In this study, we found
that the CD34+ subpopulation in the CML cell line K562 had a higher expression of SOD1 than that in the CD34 negative cells.
Knockdown of SOD1 in CD34+ cells had no significant effects on cell survival and growth, while it sensitized the CD34+ cells
to imatinib therapy. N-acetyl-L cysteine (NAC) blocked the pro-apoptotic effects of SOD1 knockdown, suggesting the antioxidant
effects of SOD1 was essential for the resistance of CD34+ cells to imatinib therapy. In summary, our results suggest that
antagonizing the enhanced endogenous antioxidant activity in leukemia stem cells sheds lights on CML therapy.
Content Type Journal ArticleCategory Original PaperDOI 10.1007/s12032-010-9529-9Authors
Li Liu, Fourth Military Medical University Department of Hematology…
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