Ponatinib: a third-generation inhibitor for the treatment of CML.

Posted by rob on September 10, 2014 under Uncategorized | Comments are off for this article

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Ponatinib: a third-generation inhibitor for the treatment of CML.

Recent Results Cancer Res. 2014;201:99-107

Authors: Wehrle J, Pahl HL, von Bubnoff N

Abstract

The establishment of imatinib as the standard therapy for CML marked the beginning of a new era of treatment. Due to occurring intolerance and resistance against the drug, developing newer inhibitors was promoted. This led to the second-generation inhibitors dasatinib, nilotinib and bosutinib. Despite all achieved improvement, all first- and second-generation inhibitors are ineffective against the BCR-ABL T315I “gatekeeper” mutation. In order to overcome this issue and to further improve the inhibitory effect, the third-generation inhibitor ponatinib was developed. Various clinical trials have been launched to study the effect of ponatinib in the clinical setting. Based on positive phase 1 and phase 2 trials, ponatinib was approved for the second-line treatment of CML and Ph+ ALL in December 2012 in the United States and in July 2013 in the European Union. Further trials investigate the potential effect of ponatinib in kinase-dependent subgroups of other malignancies. In conclusion, ponatinib has proved to be a powerful BCR-ABL inhibitor, which exhibits clinical activity both in BCR-ABL wild-type and mutant CML, including activity against the T315I mutation. Despite previous TKI failure, chronic-phase CML patients can achieve sustained remissions using the novel drug, offering a new therapeutic option in the treatment for CML.

PMID: 24756787 [PubMed - indexed for MEDLINE]

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Bosutinib: a novel second-generation tyrosine kinase inhibitor.

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Bosutinib: a novel second-generation tyrosine kinase inhibitor.

Recent Results Cancer Res. 2014;201:81-97

Authors: Isfort S, Keller-v Amsberg G, Schafhausen P, Koschmieder S, Brümmendorf TH

Abstract

Bosutinib (SKI-606) is a 4-anilino-3-quinoline carbonitrile, which acts as a dual inhibitor of Src and ABL kinases. In addition, the BCR-ABL fusion gene product, a constitutively activated tyrosine kinase which is crucial for the development of chronic myeloid leukemia (CML), is highly sensitive to bosutinib. Interestingly, distinctly lower concentrations of bosutinib are required to ablate BCR-ABL phosphorylation when compared to the first-generation tyrosine kinase inhibitor imatinib (IM). Bosutinib is a potent inhibitor of CML cell proliferation in vitro and has demonstrated promising activity in CML patients resistant or intolerant to IM as well as in newly diagnosed patients with chronic phase CML (CML-CP). Remarkably, bosutinib has been found to be capable of overcoming the majority of IM-resistant BCR-ABL mutations. Bosutinib has the potency to induce deep and fast responses in second- and third-/fourth-line treatment, and as a consequence, the drug has recently been licensed for patients previously treated with one or more tyrosine kinase inhibitor(s) and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options. Due to its potency and differing toxicity profile, it promises to be a good therapeutic option for a defined cohort of patients. The most common side effects are gastrointestinal with most of the patients suffering from nausea, vomiting, or diarrhea. For the most part, these gastrointestinal symptoms occur early after treatment initiation, are manageable, and often self-limiting. Continuous monitoring of liver enzymes upon treatment initiation is necessary during bosutinib treatment. In addition to CML treatment, bosutinib has shown some efficacy in selected patients suffering from advanced-stage solid tumors. In conclusion, bosutinib is a promising novel small molecule inhibitor approved now for targeted therapy of CML and in clinical development for other malignancies.

PMID: 24756786 [PubMed - indexed for MEDLINE]

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Nilotinib.

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Nilotinib.

Recent Results Cancer Res. 2014;201:67-80

Authors: Ostendorf BN, le Coutre P, Kim TD, Quintás-Cardama A

Abstract

Targeted therapy of Philadelphia chromosome-positive chronic myeloid leukemia (CML) using the tyrosine kinase inhibitor imatinib mesylate has been one of the most striking achievements in modern cancer medicine. However, while imatinib can establish long-term remission in many cases, resistance to or intolerance of imatinib is eventually experienced by a substantial number of patients. Subsequent advances have led to the development of novel tyrosine kinase inhibitors (TKIs). One such inhibitor, nilotinib, was rationally designed to increase its affinity and specificity for the oncogenic tyrosine kinase Bcr-Abl compared with imatinib and has been shown to be effective after imatinib failure. Recently, nilotinib has been shown to be more effective when used as first-line therapy of chronic phase CML.

PMID: 24756785 [PubMed - indexed for MEDLINE]

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Dasatinib.

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Dasatinib.

Recent Results Cancer Res. 2014;201:27-65

Authors: Lindauer M, Hochhaus A

Abstract

Dasatinib is an orally available short-acting dual ABL/SRC tyrosine kinase inhibitor (TKI). It potently inhibits BCR-ABL and SRC family kinases (SRC, LCK, YES, FYN), but also c-KIT, PDGFR-? and PDGFR-?, and ephrin receptor kinase. Dasatinib is an effective treatment for chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Both diseases are characterized by a constitutively active tyrosine kinase; BCR-ABL. Dasatinib inhibits BCR-ABL with greater potency compared with other BCR-ABL inhibitors and is active in CML resistant or intolerant to imatinib. Dasatinib is approved for the treatment of CML (all phases) and for the treatment of Ph+ ALL, resistant or intolerant to prior imatinib treatment. Randomized trial data in CML show that first-line dasatinib provides superior responses compared with imatinib and enables patients to achieve early, deep responses, correlated with improved longer-term outcomes. A once-daily dose of 100 mg in chronic phase CML results in high hematologic and molecular remission rates and prolongation of survival. In accelerated and blastic phase of CML, as well as in Ph+ ALL, complete hematologic and cytogenetic remissions frequently occur. Remissions however are very short. In these patients, once-daily 140 mg is the recommended dose. The effect of dasatinib in other malignancies including solid tumors is subject of clinical studies. Regardless of many clinical trials in different tumor types and in different combinations of dasatinib with other agents, the role of dasatinib in the treatment of solid tumors has not yet been defined. Side effects of dasatinib are frequent but mostly moderate and manageable and include cytopenias and pleural effusions. The review presents the preclinical and clinical activity of dasatinib with a focus on clinical studies in CML.

PMID: 24756784 [PubMed - indexed for MEDLINE]

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Omacetaxine for treatment-resistant or treatment-intolerant adult chronic myeloid leukemia.

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Omacetaxine for treatment-resistant or treatment-intolerant adult chronic myeloid leukemia.

Am J Health Syst Pharm. 2014 Feb 15;71(4):279-88

Authors: Chung C

Abstract

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, and safety of a first-in-class protein synthesis inhibitor for use in treatment-resistant chronic myeloid leukemia (CML) are reviewed.

SUMMARY: Omacetaxine mepesuccinate (Synribo, Teva Pharmaceuticals) is a potent plant alkaloid isolated from Cephalotaxus (Chinese yew tree) species. It has a mechanism of action distinct from that of the standard first-line therapy for CML, tyrosine kinase inhibitors (TKIs), and has demonstrated efficacy in adult patients with chronic- or accelerated-phase CML who develop intolerance to two or more TKIs or experience multiple TKI treatment failures. Two open-label Phase II trials (combined n = 108) demonstrated that omacetaxine produced a major cytogenetic response in 18.4% of patients with chronic-phase CML and a major hematologic response in 14.3% of patients with accelerated-phase CML (median duration of reponse, 12.5 and 4.7 months, respectively). Symptom improvement or improved overall survival in omacetaxine-treated patients has not been demonstrated. In clinical trials to date, the most common grade 1-4 adverse reactions included thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, and asthenia. The drug is administered subcutaneously on an intermittent schedule (14 days on, 14 days off during induction; 7 days on, 21 days off during maintenance). Research to better delineate omacetaxine’s optimal role in the management of CML and other hematologic malignancies (e.g., acute myelogenic leukemia) is ongoing.

CONCLUSION: Omacetaxine, a novel protein synthesis inhibitor, provides an alternative therapy for patients with CML who have experienced TKI treatment failures or are intolerant of two or more TKIs.

PMID: 24481153 [PubMed - indexed for MEDLINE]

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Professor John M. Goldman, CML pioneer 1938-2013.

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Professor John M. Goldman, CML pioneer 1938-2013.

Int J Hematol. 2014 Feb;99(2):103-4

Authors: Gale RP

PMID: 24414339 [PubMed - indexed for MEDLINE]

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A novel approach to total skin irradiation using helical TomoTherapy.

Posted by rob on September 7, 2014 under Uncategorized | Comments are off for this article

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A novel approach to total skin irradiation using helical TomoTherapy.

Pract Radiat Oncol. 2014 September – October;4(5):330-335

Authors: Sarfehnia A, Poon E, Davis SD, Fleming A, Mitchell D, Freeman CR

Abstract

PURPOSE: To describe our experience with a novel technique for total skin irradiation using helical TomoTherapy (Accuray, Sunnyvale, CA).

METHODS AND MATERIALS: An infant with refractory acute myelogenous leukemia with extensive cutaneous involvement was given total skin irradiation using inverse-planned helical tomotherapy. Quality assurance tests to determine the deliverability of the technique and the accuracy of dose estimation at the superficial skin level were devised and performed. Daily megavoltage imaging, tomotherapy plan adaptive evaluation, in vivo skin dose measurements, and cumulative dose summation were tools employed to assess the quality of treatment and positioning reproducibility on a daily basis.

RESULTS: The quality assurance checks showed that tomotherapy can indeed be used for total skin irradiation in cases where conventional electron treatment delivery is not possible. However, the overestimation of absorbed dose near surface by the treatment planning software must be quantified and taken into account using in-phantom and in vivo dosimetry techniques with appropriate detectors. Daily imaging allows for superior positioning, while daily plan adaptive and dose summations based on the plan adaptive calculations allow for evaluation of the treatment delivery.

CONCLUSIONS: An infant has been treated successfully using helical TomoTherapy for total skin irradiation prior to allogeneic stem cell transplant. The course of treatment was uncomplicated and the patient is doing well more than 15 months following therapy.

PMID: 25194102 [PubMed - as supplied by publisher]

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Anti-rheumatic agent auranofin induced apoptosis in chronic myeloid leukemia cells resistant to imatinib through both Bcr/Abl-dependent and -independent mechanisms.

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Anti-rheumatic agent auranofin induced apoptosis in chronic myeloid leukemia cells resistant to imatinib through both Bcr/Abl-dependent and -independent mechanisms.

Oncotarget. 2014 Aug 22;

Authors: Chen X, Shi X, Zhao C, Li X, Lan X, Liu S, Huang H, Liu N, Liao S, Zang D, Song W, Liu Q, Carter BZ, Dou QP, Wang X, Liu J

Abstract

Resistance to Imatinib mesylate (IM) is an emerging problem for patients with chronic myelogenous leukemia (CML). T315I mutation in the Bcr-Abl is the predominant mechanism of the acquired resistance to IM and second generation tyrosine kinase inhibitors (TKI). Therefore it is urgent to search for new measures to overcome TKI-resistance. Auranofin (AF), clinically used to treat rheumatic arthritis, was recently approved by US Food and Drug Administration for Phase II clinical trial to treat cancer. In contrast to the reports that AF induces apoptosis by increasing intracellular reactive oxygen species (ROS) levels via inhibiting thioredoxin reductase, our recent study revealed that AF-induced apoptosis depends on inhibition of proteasomal deubiquitinases (UCHL5 and USP14). Here we report that (i) AF induces apoptosis in both Bcr-Abl wild-type cells and Bcr-Abl-T315I mutation cells and inhibits the growth of IM-resistant Bcr-Abl-T315I xenografts in vivo; (ii) AF inhibits Bcr-Abl through both downregulation of Bcr-Abl gene expression and Bcr-Abl cleavage mediated by proteasome inhibition-induced caspase activation; (iii) proteasome inhibition but not ROS is required for AF-induced caspase activation and apoptosis. These findings support that AF overcomes IM resistance through both Bcr/Abl-dependent and -independent mechanisms, providing great clinical significance for cancer treatment.

PMID: 25193854 [PubMed - as supplied by publisher]

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Bilateral Sequential Dacryocystitis in a Patient With Graft-Versus-Host Disease.

Posted by rob on September 6, 2014 under Uncategorized | Comments are off for this article

Bilateral Sequential Dacryocystitis in a Patient With Graft-Versus-Host Disease.

Ophthal Plast Reconstr Surg. 2014 Sep 4;

Authors: Campbell AA, Jakobiec FA, Rashid A, Dana R, Yoon MK

Abstract

A 29-year-old woman with a history of 2 bone marrow transplants for acute myelogenous leukemia developed bilateral sequential dacryocystitis in the context of known ocular graft-versus-host disease. With each infection, the patient underwent uneventful dacryocystorhinostomy. Postoperatively, she developed severe dry eye disease requiring replacement of punctal plugs and use of a prosthetic replacement of the ocular surface ecosystem lens. Histopathologic and immunohistochemical examination of the lacrimal sac showed a dense diffuse nonfollicular lymphocytic subepithelial infiltrate in the lacrimal sac that contained moderately more T-cells than B-cells. This is the first report of acute dacryocystitis associated with graft-versus-host disease. The authors caution that similar patients may develop worsening of ocular surface dryness due to restoration of normal lacrimal outflow.

PMID: 25192327 [PubMed - as supplied by publisher]

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Assessing disease burden in patients with classic MPNs.

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Assessing disease burden in patients with classic MPNs.

Best Pract Res Clin Haematol. 2014 Jun;27(2):107-119

Authors: Geyer H, Mesa RA

Abstract

Myeloproliferative neoplasm (MPN) disorders including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF), are recognized amongst the world of malignancies for their unique disease-burden profiles. Symptom management remains a prime directive for all MPN disorders. Limited by the dramatic heterogeneity and disparate severity amongst symptoms, only recently have researchers possessed the scoring tools necessary to quantify the MPN symptom burden and investigate its role in patient prognosis. In addition to symptom management, clinicians are also tasked with managing the numerous complications that arise from MPN progression including splenomegaly, cytopenias, thrombotic and hemorrhagic events and transformation to MF (from PV or ET) or acute myelogenous leukemia. In this article, we discuss the pleiotropic solidarity of the MPN symptom profile, inherent complications that define the disorders, available patient-reported outcome tools, the role of risk-scoring algorithms and open arenas for ongoing MPN symptom research.

PMID: 25189722 [PubMed - as supplied by publisher]

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Rapid Sequential Gain of ABL1 Kinase Domain Mutations with a Complex Karyotype in the Progression of Chronic Myelogenous Leukemia.

Posted by rob on September 5, 2014 under Uncategorized | Comments are off for this article

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Rapid Sequential Gain of ABL1 Kinase Domain Mutations with a Complex Karyotype in the Progression of Chronic Myelogenous Leukemia.

Ann Lab Med. 2014 Sep;34(5):399-401

Authors: Chung Y, Eom HS, Lee H, Park S, Shim H, Cho EH, Kong SY

PMID: 25187896 [PubMed - in process]

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Therapy-related chronic myelogenous leukemia following RFM therapy in a patient with follicular lymphoma.

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Therapy-related chronic myelogenous leukemia following RFM therapy in a patient with follicular lymphoma.

Rinsho Ketsueki. 2014 Aug;55(8):970-4

Authors: Shibazaki M, Sumi M, Takeda W, Kirihara T, Kurihara T, Sato K, Ueki T, Hiroshima Y, Ueno M, Ichikawa N, Mori Y, Kobayashi H

Abstract

Therapy-related myelodysplastic syndrome and acute myelogenous leukemia are increasingly being recognized as treatment complications in patients receiving chemotherapy or radiotherapy for previous neoplasms. However, therapy-related chronic myelogenous leukemia is relatively rare. A 61-year-old woman with a history of radiation therapy for breast cancer had previously, in 2007, received 4 courses of chemotherapy (RFM: rituximab, fludarabine, and mitoxantrone) for follicular lymphoma. In 2010, she was diagnosed with chronic-phase chronic myelogenous leukemia (CML) with Philadelphia chromosome but no other cytogenetic anomalies. Although a complete cytogenetic response (CCyR) was achieved with imatinib therapy, she developed leukocytosis with lymphoblasts and lymphoid crisis was diagnosed in January 2013. G-banded karyotyping showed 45, XX, -7, t, (9;22)(q33;q11.2). Unrelated bone marrow stem cell transplantation was performed after she had achieved a CCyR with dasatinib therapy. Polymerase chain reaction detected no major bcr/abl transcript in her bone marrow 42 days after transplantation. The majority of secondary leukemias resulting from the use of cytotoxic drugs can be divided into two well-defined groups depending on whether the patient has received alkylating agents or topoisomerase II inhibitors. However, concerns regarding the leukemogenic potential of fludarabine-based chemotherapy are growing. The potential risk of therapy-related leukemias including CML needs to be considered following fludarabine-based chemotherapy.

PMID: 25186488 [PubMed - in process]

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[Efficacy and safety analysis of interferon combined with imatinib in treating chronic myeloid leukemia].

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[Efficacy and safety analysis of interferon combined with imatinib in treating chronic myeloid leukemia].

Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014 Apr;22(2):304-9

Authors: Liu Y, Bao EN, Zhong WW, Lu XC, Zhu HL

Abstract

Imatinib has been recognized as the frontline therapy drug in chronic myeloid leukemia (CML), however, only limited patients could achieve complete molecular remission (CMR). Recent clinical and basic proofs indicated an improved treatment outcome by the combination of interferon and Imatinib. This study was purposed to evaluated systematically the efficacy and safety of interferon plus Imatinib in patients with CML. Data from relative clinical trials were from clinical trial of gov and Cochrane Collaboration. A comprehensive literature search was performed from data bases such as pubMed and EM. The results indicated that 7 clinical trials and 12 research papers met the criteria enrolled in study, included 697 cases in total. The combination group had higher complete cytogenetic remission (CCgR) rate than imatinib alone at 6 months (58% vs 42%; P = 0.0001) and 12 months (74% vs 68%; P = 0.004). The major molecular remission (MMR) rate was also higher in the combination group at 6 months (58% vs 34%; P = 0.0001) and 12 months (66% vs 47%; P < 0.0001). Furthermore, compared with single drug, the combination group had superior CMR rate at 6 months (13% vs 2%; P = 0.0002) and 12 months (14% vs 5%; P = 0.0009). The major adverse effects of combination therapy were rash, asthenia, edema and musculoskeletal events, and combination therapy was more prone to inducing neutropenia, thrombocytopenia and mild anemia. It is concluded that compared with Imatinib alone, the combination of interferon and Imatinib has better clinical efficacy in treating CML with earlier cytogenetic and molecular remission. It is also a safe therapy in spite of slightly weaker tolerance than single drug therapy.

PMID: 24762996 [PubMed - indexed for MEDLINE]

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FDA halts then allows sales of Ariad’s leukemia medication.

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FDA halts then allows sales of Ariad’s leukemia medication.

Nat Biotechnol. 2014 Jan;32(1):9-11

Authors: Senior M

PMID: 24406915 [PubMed - indexed for MEDLINE]

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Study of imatinib treatment patterns and outcomes among US veteran patients with Philadelphia chromosome-positive chronic myeloid leukemia.

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Study of imatinib treatment patterns and outcomes among US veteran patients with Philadelphia chromosome-positive chronic myeloid leukemia.

J Oncol Pract. 2013 Sep;9(5):e212-9

Authors: Vander Velde N, Chen L, Guo A, Sharma H, Marynchenko M, Wu EQ, Liu J, Yang H, Shi L

Abstract

PURPOSE: This study investigated the treatment patterns and outcomes for US veteran patients with chronic myeloid leukemia-chronic phase (CML-CP) initiated on imatinib (IM).

PATIENTS AND METHODS: Patients (age?18 years) with at least one CML diagnosis (International Classification of Diseases, Ninth Edition Clinical Modification: 205.1x) during the period January 1, 2000, to June 30, 2011, and initiated on IM as first-line therapy were identified in the VISN 16 data warehouse (N=137). Accelerated and blastic phases (AP/BP) were identified on the basis of WHO classification using complete blood count (CBC) data. Rates of IM dose adjustment, discontinuation, and switching to another drug therapy were estimated. Time to discontinuation, progression to AP/BP, and survival were assessed using Kaplan-Meier analysis (KM).

RESULTS: During follow-up, 19.0% of patients had at least one dose increase; of these, 19.2% switched to another therapy. Dose reductions occurred in 25.6% of patients. Among patients who discontinued IM (n=74; 54.0%), whereas 16.2% switched to other therapies, 27.0% neither restarted IM nor switched to other therapies. KM showed that 25.6% and 42.4% of patients discontinued IM treatment by year 1 and 2, and 8.1% and 16.0% demonstrated disease progression by year 1 and 2, respectively. Among patients who experienced disease progression (n=28), 32.1% continued IM postprogression, 32.1% discontinued IM before progression, 28.6% discontinued IM postprogression without switching, and 7.1% switched to other therapies postprogression. The mortality rates were 3.0% and 9.5% after IM initiation, and 21.7% and 42.7% after disease progression by year 1 and 2, respectively.

CONCLUSION: In this veteran population, a substantial number of IM-treated patients, including those with disease progression, either discontinued or interrupted IM use without switching to other therapies.

PMID: 23943889 [PubMed - indexed for MEDLINE]

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Investigating evolutionary perspective of carcinogenesis with single-cell transcriptome analysis.

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Investigating evolutionary perspective of carcinogenesis with single-cell transcriptome analysis.

Chin J Cancer. 2013 Dec;32(12):636-9

Authors: Zhang X, Zhang C, Li Z, Zhong J, Weiner LP, Zhong JF

Abstract

We developed phase-switch microfluidic devices for molecular profiling of a large number of single cells. Whole genome microarrays and RNA-sequencing are commonly used to determine the expression levels of genes in cell lysates (a physical mix of millions of cells) for inferring gene functions. However, cellular heterogeneity becomes an inherent noise in the measurement of gene expression. The unique molecular characteristics of individual cells, as well as the temporal and quantitative information of gene expression in cells, are lost when averaged among all cells in cell lysates. Our single-cell technology overcomes this limitation and enables us to obtain a large number of single-cell transcriptomes from a population of cells. A collection of single-cell molecular profiles allows us to study carcinogenesis from an evolutionary perspective by treating cancer as a diverse population of cells with abnormal molecular characteristics. Because a cancer cell population contains cells at various stages of development toward drug resistance, clustering similar single-cell molecular profiles could reveal how drug-resistant sub-clones evolve during cancer treatment. Here, we discuss how single-cell transcriptome analysis technology could enable the study of carcinogenesis from an evolutionary perspective and the development of drug-resistance in leukemia. The single-cell transcriptome analysis reported here could have a direct and significant impact on current cancer treatments and future personalized cancer therapies.

PMID: 23706768 [PubMed - indexed for MEDLINE]

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Antimicrobial activity against periodontopathogenic bacteria, antioxidant and cytotoxic effects of various extracts from endemic Thermopsis turcica.

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Antimicrobial activity against periodontopathogenic bacteria, antioxidant and cytotoxic effects of various extracts from endemic Thermopsis turcica.

Asian Pac J Trop Biomed. 2014 Jul;4(7):505-14

Authors: Bali EB, Aç?k L, Akca G, Sarper M, Elçi MP, Avcu F, Vural M

Abstract

OBJECTIVE: To investigate the in vitro antimicrobial potential of Thermopsis turcica Kit Tan, Vural & Küçüködük against periodontopathogenic bacteria, its antioxidant activity and cytotoxic effect on various cancer cell lines.

METHODS: In vitro antimicrobial activities of ethanol, methanol, ethyl acetate (EtAc), n-hexane and water extracts of Thermopsis turcica herb against periodontopathogenic bacteria, Aggregatibacter actinomycetemcomitans ATCC 29523 and Porphyromonas gingivalis ATCC 33277 were tested by agar well diffusion, minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). Antioxidant properties of the extracts were evaluated by 1,1-diphenyl-2-picryl-hydrazyl radical scavenging activity and ?-carotene bleaching methods. Amounts of phenolic contents of the extracts were also analysed by using the Folin-Ciocalteu reagent. Additionally, cytotoxic activity of the extracts on androgen-insensitive prostate cancer, androgen-sensitive prostate cancer, chronic myelogenous leukemia and acute promyelocytic leukemia human cancer cell lines were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Human gingival fibroblast cells were used as a control.

RESULTS: Our data showed that EtAc extract had the highest antimicrobial effect on Aggregatibacter actinomycetemcomitans (MIC: 1.562 mg/mL, MBC: 3.124 mg/mL) and Porphyromonas gingivalis (MIC: 0.781 mg/mL, MBC: 1.562 mg/mL). In antioxidant assays, EtAc extract exhibited also the highest radical scavenging activity [IC50=(30.0±0.3) µg/mL] and the highest inhibition [(74.35±0.30)%] against lineloic acide oxidation. The amount of phenolic content of it was also the highest [(162.5±1.2) µg/mg gallic acid]. In cytotoxic assay, only ethanol [IC50=(80.00±1.21) µg/mL] and EtAc extract [IC50=(70.0±0.9) µg/mL] were toxic on acute promyelocytic leukemia cells at 20-100 µg/mL (P<0.05). However, no toxic effect was observed on human gingival fibroblast cells.

CONCLUSIONS: According to our findings, owing to its antioxidant and cytotoxic potential, EtAc extract might include anticancer agents for acute promyelocytic leukemia.

PMID: 25183268 [PubMed]

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Novel Approach for Coexpression Analysis of E2F1-3 and MYC Target Genes in Chronic Myelogenous Leukemia.

Posted by rob on September 3, 2014 under Uncategorized | Comments are off for this article

Novel Approach for Coexpression Analysis of E2F1-3 and MYC Target Genes in Chronic Myelogenous Leukemia.

Biomed Res Int. 2014;2014:439840

Authors: Wang F, Chan LW, Cho WC, Tang P, Yu J, Shyu CR, Tsui NB, Wong SC, Siu PM, Yip SP, Yung BY

Abstract

Background. Chronic myelogenous leukemia (CML) is characterized by tremendous amount of immature myeloid cells in the blood circulation. E2F1-3 and MYC are important transcription factors that form positive feedback loops by reciprocal regulation in their own transcription processes. Since genes regulated by E2F1-3 or MYC are related to cell proliferation and apoptosis, we wonder if there exists difference in the coexpression patterns of genes regulated concurrently by E2F1-3 and MYC between the normal and the CML states. Results. We proposed a method to explore the difference in the coexpression patterns of those candidate target genes between the normal and the CML groups. A disease-specific cutoff point for coexpression levels that classified the coexpressed gene pairs into strong and weak coexpression classes was identified. Our developed method effectively identified the coexpression pattern differences from the overall structure. Moreover, we found that genes related to the cell adhesion and angiogenesis properties were more likely to be coexpressed in the normal group when compared to the CML group. Conclusion. Our findings may be helpful in exploring the underlying mechanisms of CML and provide useful information in cancer treatment.

PMID: 25180182 [PubMed - as supplied by publisher]

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Granulocytic sarcoma with compressive myelopathy: a rare presentation of chronic myelogenous leukemia.

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Granulocytic sarcoma with compressive myelopathy: a rare presentation of chronic myelogenous leukemia.

J Clin Diagn Res. 2014 Jul;8(7):QD03-4

Authors: Ganapule AP, Viswabandya A, Jasper A, Patel P, Kokil G

Abstract

Granulocytic sarcoma occurs most commonly in acute myelogenous leukemia. The appearance of granulocytic sarcoma in chronic myelogenous leukemia signals accelerated phase/ blast transformation. This is a rare case of undiagnosed chronic myelogenous leukemia with granulocytic sarcoma causing cord compression, which went into tumour lysis syndrome requiring dialysis after starting of steroids and radiotherapy. A 43-year-old male presented in emergency department with acute onset of flaccid paralysis. On clinical examination, there was hepatosplenomegaly and lower motor neuron paralysis in the lower limbs. The peripheral smear was consistent with chronic myelogenous leukemia in chronic phase. The MRI spine revealed para-spinal and epidural masses causing cord compression and the biopsy from the paraspinal mass was consistent with granulocytic sarcoma.

PMID: 25177619 [PubMed]

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Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia.

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Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia.

Mol Ther. 2014 Sep 1;

Authors: Wang QS, Wang Y, Lv HY, Han QW, Fan H, Guo B, Wang LL, Han WD

Abstract

We conducted a clinical trial to assess the feasibility and efficacy of CD33-directed chimeric antigen receptor-modified T cells (CART-33) for the treatment of refractory acute myelogenous leukemia (AML). A 41-year-old male patient with AML was enrolled and received a total of 1.12×10(9) autologous CART-33 cells, of which approximately 38% were transduced with CAR. The CART-33 infusion alone induced rigorous chills and fevers; drastic fluctuations of his preexisting pancytopenia; elevated serum cytokine levels, including IL-6, IL-8, TNF-?, and IFN-? slight transient hyperbilirubinemia within two weeks; a subsequent intermittent moderate fever; and reversed fluctuation of the pancytopenia. A marked decrease of blasts in the bone marrow was observed upon examination two weeks after therapy, and there was a gradual increase until florid disease progression occurred at nine weeks after the cell infusion. These observations warrant further research on CART-33 treatment in refractory AML and may spur efforts to extend the CART-33-induced tumor burden to the preparation of other intensive strategies, such as hematopoietic stem cell transplantation. This study is registered at www.ClinicalTrials.gov as NCT01864902.Molecular Therapy (2014); doi:10.1038/mt.2014.164.

PMID: 25174587 [PubMed - as supplied by publisher]

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