Linear antimicrobial peptides from Ectatomma quadridens ant venom.

Posted by rob on September 16, 2014 under Uncategorized | Comments are off for this article

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Linear antimicrobial peptides from Ectatomma quadridens ant venom.

Biochimie. 2014 Sep 11;

Authors: Pluzhnikov KA, Kozlov SA, Vassilevski AA, Vorontsova OV, Feofanov AV, Grishin EV

Abstract

Three species of the ant subfamily Ponerinae (Paraponera clavata, Ectatomma quadridens and Ectatomma tuberculatum) were investigated for the growth inhibition of Gram-positive and Gram-negative bacteria. It was shown that the venom of E. quadridens and its peptide fraction in particular possess marked antibacterial action. Three linear antimicrobial peptides sharing low similarity to the well-known ponericin peptides were isolated from this ant venom by means of size-exclusion and reversed-phase chromatography. The peptides showed antimicrobial activity at low micromolar concentrations. Their primary structure was established by direct Edman sequencing in combination with mass spectrometry. The most active peptide designated ponericin-Q42 was chemically synthesized. Its secondary structure was investigated in aqueous and membrane-mimicking environment, and the peptide was shown to be partially helical already in water, which is unusual for short linear peptides. Analysis of its activity on different bacterial strains, human erythrocytes and chronic myelogenous leukemia K562 cells revealed that the peptide shows broad spectrum cytolytic activity at micromolar and submicromolar concentrations. Ponericin-Q42 also possesses weak toxic activity on flesh fly larvae with LD50 of ?105 ?g/g.

PMID: 25220871 [PubMed - as supplied by publisher]

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Dynamics of chronic myeloid leukemia response to dasatinib, nilotinib, and high-dose imatinib.

Posted by rob on September 14, 2014 under Uncategorized | Comments are off for this article

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Dynamics of chronic myeloid leukemia response to dasatinib, nilotinib, and high-dose imatinib.

Haematologica. 2014 Sep 12;

Authors: Olshen A, Tang M, Cortes J, Gonen M, Hughes T, Branford S, Quintás-Cardama A, Michor F

Abstract

Treatment with the tyrosine kinase inhibitor imatinib represents the standard of care for newly diagnosed patients with chronic myeloid leukemia. In recent years, several second generation inhibitors – such as dasatinib and nilotinib – have become available that promise to overcome some of the mutations associated with acquired resistance in these patients. Despite eliciting similar clinical responses, the molecular effects of these agents on different subpopulations of leukemic cells remain incompletely understood. Furthermore, the consequences of using high-dose imatinib therapy have not been investigated in detail. Here we utilized clinical data from patients treated with dasatinib, nilotinib, or high-dose imatinib, together with a statistical data analysis and mathematical modeling approach, to investigate the molecular treatment response of leukemic cells to these agents. We found that these drugs elicit very similar responses if administered front-line. However, the patient population displays significantly different kinetics when treated second line, both in terms of differences between front-line and second line treatment for the same drug, and among agents when used second-line. We then utilized a mathematical framework describing the behavior of four differentiation levels of leukemic cells during therapy to predict the treatment response kinetics for the different patient cohorts. The dynamics of BCR-ABL1 clearance observed in our study suggest that the use of standard or high-dose imatinib or a second generation TKI such as nilotinib or dasatinib elicit similar responses when administered as frontline therapy for patients with CML in chronic phase.

PMID: 25216683 [PubMed - as supplied by publisher]

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Tibetan Medicine for Cancer: An Overview and Review of Case Studies.

Posted by rob on September 12, 2014 under Uncategorized | Comments are off for this article

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Tibetan Medicine for Cancer: An Overview and Review of Case Studies.

Integr Cancer Ther. 2014 Sep 10;

Authors: Bauer-Wu S, Lhundup Kachupa T, Tidwell T, Lhadon Menrampa T, Ozawa-de Silva C, Dolma Menrampa J, Dorjee Menrampa P, Neshar Menrampa DR, Sangmo Menrampa R, Yeshi Kachupa T

Abstract

Introduction: Tibetan medicine (TM) is a whole systems medical approach that has had growing interest in the West. However, minimal research, particularly with cancer, has been conducted. The purpose of this article is to provide an overview of TM and describe a clinical case review study to obtain preliminary evidence of TM’s safety and effect on patients treated for cancer or hematologic disorders. Methods: A retrospective case review was conducted in India and cases met the following inclusion criteria: (a) confirmed diagnosis of cancer or hematologic disorder by standard Western biomedical diagnostic tests, (b) either treated exclusively with TM or received insufficient Western treatment followed by TM and (c) were in remission or had stable disease at least 2 years after start of TM. Results: Three cases were identified, 1 solid tumor and 2 hematologic diseases: Case 1-poorly to moderately differentiated adenocarcinoma of the stomach, positive lymph nodes and mucosal infiltration, with clear scans and excellent quality of life 29 months later ; Case 2-chronic myelogenous leukemia with normalization of hematologic labs within 3 months of starting TM and stable 4 years later; and Case 3-red cell aplasia improved significantly and reversed dependence on blood transfusions with TM. None of the cases experienced demonstrable adverse effects from TM. Conclusions: This limited case review found TM to be safe and have positive effects on quality of life and disease regression and remission in patients with cancer and blood disorders. Further exploration and investigation using rigorous methods is warranted.

PMID: 25209591 [PubMed - as supplied by publisher]

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DNA copy number alterations mark disease progression in paediatric chronic myeloid leukaemia.

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DNA copy number alterations mark disease progression in paediatric chronic myeloid leukaemia.

Br J Haematol. 2014 Jul;166(2):250-3

Authors: van der Sligte NE, Krumbholz M, Pastorczak A, Scheijen B, Tauer JT, Nowasz C, Sonneveld E, de Bock GH, Meeuwsen-de Boer TG, van Reijmersdal S, Kuiper RP, Bradtke J, Metzler M, Suttorp M, de Bont ES, van Leeuwen FN

Abstract

Early recognition of children with chronic phase chronic myeloid leukaemia (CML-CP) at risk for developing a lymphoid blast crisis (LyBC) is desirable, because therapy options in CML-LyBC are limited. We used Multiplex Ligation-dependent Probe Amplification to determine whether B-cell lymphoid leukaemia-specific copy number alterations (CNAs) (e.g. IKZF1, PAX5, CDKN2A deletions) could be detected in CML-CP and may be used to predict disease progression to LyBC. CNAs were detected in all patients with CML-LyBC, but in none of the 77 patients with CML-CP. Based on this study we conclude that CNAs remain a hallmark of disease progression.

PMID: 24673583 [PubMed - indexed for MEDLINE]

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Comparison of unrelated cord blood transplantation and HLA-matched sibling hematopoietic stem cell transplantation for patients with chronic myeloid leukemia in advanced stage.

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Comparison of unrelated cord blood transplantation and HLA-matched sibling hematopoietic stem cell transplantation for patients with chronic myeloid leukemia in advanced stage.

Biol Blood Marrow Transplant. 2013 Dec;19(12):1708-12

Authors: Zheng C, Tang B, Yao W, Tong J, Zhu X, Song K, Geng L, Liu H, Sun Z

Abstract

This is the first report to present a clinical comparison of unrelated cord blood transplantation (CBT) and HLA-matched sibling allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia (CML) in advanced stage (accelerated phase or blast crisis). A total of 32 consecutive patients with advanced CML received unrelated CBT (n= 16) or HLA-matched sibling allogeneic peripheral blood stem cell or bone marrow transplantation (allo-PBSCT/BMT) (n = 16) between 2002 and 2011. The median day to neutrophil engraftment and the median day to platelet engraftment were longer in the unrelated CBT group. The cumulative incidence of grades 1 to 2 acute graft-versus-host disease (aGVHD), grades 3 to 4 aGVHD, and chronic graft-versus-host disease did not differ significantly between the 2 cohorts. The cumulative incidence of transplantation-related mortality (TRM) at day +180 was higher in CBT group (37.5% versus 12.5%, P = .013). The risk of relapse was lower in CBT patients compared with that of allo-PBSCT/BMT patients (14.2% versus 42.7%, P = .03). The long-term survival in CBT group patients was slightly better than that of allo-PBSCT/BMT group, although the difference did not reach statistical significance: the 5-year overall survival for CBT patients and allo-PBSCT/BMT patients was 62.5% and 48.6%, respectively (P= .10), whereas the 5-year leukemia-free-survival rate was 50% and 40.5%, respectively (P = .12). Our comparisons suggest that patients with advanced CML receiving unrelated CBT had a lower relapse rate, a slightly better long-term survival, but a higher early TRM than those receiving HLA-matched related allo-PBSCT/BMT.

PMID: 24060407 [PubMed - indexed for MEDLINE]

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Orbital Mass Secondary to Acute Lymphoblastic Leukaemia in a Child: A Rare Presentation.

Posted by rob on September 11, 2014 under Uncategorized | Comments are off for this article

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Orbital Mass Secondary to Acute Lymphoblastic Leukaemia in a Child: A Rare Presentation.

Orbit. 2014 Sep 10;:1-3

Authors: Chaudhry SR, Kreis AJ, Underhill HC, Madge SN

Abstract

Abstract We report the case of a 3-year-old child, who presented with lid swelling which progressed to proptosis of the left eye. He also had systemic symptoms of fatigue and weight loss. An examination revealed hepatosplenomegaly and lymph node enlargement. Investigations showed a peripheral smear with blast cells, which were also revealed through a bone marrow biopsy. A CT scan showed a mass lesion in the left orbit that had infiltrated into the surrounding tissues. He was diagnosed with acute lymphoblastic leukaemia (ALL) with left-sided orbital mass secondary to it. Haematogenous masses in the orbit are commonly due to granulocytic sarcomas, which are usually associated with acute myelogenous leukaemia (AML), not ALL, and are rare especially when they precede systemic disease.

PMID: 25207876 [PubMed - as supplied by publisher]

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Myeloproliferative disorders.

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Myeloproliferative disorders.

Emerg Med Clin North Am. 2014 Aug;32(3):597-612

Authors: Meier B, Burton JH

Abstract

The emergency providers generally encounters myeloproliferative disorders (MPNs) in 1 of 2 ways: as striking laboratory abnormalities of seeming unknown consequence, or in previously diagnosed patients presenting with complications. The course of patients with MPNs is highly variable, but major complications can arise. Emergent conditions related to hyperviscosity need to be recognized early and treated aggressively. Rapid hydration, transfusion, cytoreduction, and early hematology consultation can be lifesaving. Likewise, although management is not altered, a high index of suspicion for thrombotic complications is required in patients with known MPNs as these are a significant cause of morbidity and mortality.

PMID: 25060252 [PubMed - indexed for MEDLINE]

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Acute leukemia.

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Acute leukemia.

Emerg Med Clin North Am. 2014 Aug;32(3):579-96

Authors: Rose-Inman H, Kuehl D

Abstract

Although great progress has been made in the understanding and treatment of acute leukemia, this disease has not been conquered. For emergency providers (EPs), the presentation of these patients to an emergency department presents a host of challenges. A patient may present with a new diagnosis of leukemia or with complications of the disease process or associated chemotherapy. It is incumbent on EPs to be familiar with the manifestations of leukemia in its various stages and maintain some suspicion for this diagnosis, given the nebulous and insidious manner in which leukemia can present.

PMID: 25060251 [PubMed - indexed for MEDLINE]

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[Current diagnostic requirements in chronic myeloid leukemia].

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[Current diagnostic requirements in chronic myeloid leukemia].

Wien Med Wochenschr. 2013 Nov;163(21-22):477-94

Authors: Lion T, Webersinke G, Kastner U, Seger C, Mitterbauer-Hohendanner G, Gastl G

Abstract

In patients with chronic myeloid leukemia, high-quality diagnostics is of paramount importance for the surveillance of treatment efficacy. The availability of new tyrosine kinase inhibitors providing more rapid and deeper responses requires the employment of standardized and highly sensitive diagnostic methods to ensure optimal monitoring of the patients. This review presents the current international diagnostic standards and the certified laboratories in Austria.

PMID: 24081749 [PubMed - indexed for MEDLINE]

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CXCL12(+) stromal cells as bone marrow niche for CD34(+) hematopoietic cells and their association with disease progression in myelodysplastic syndromes.

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

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CXCL12(+) stromal cells as bone marrow niche for CD34(+) hematopoietic cells and their association with disease progression in myelodysplastic syndromes.

Lab Invest. 2014 Sep 8;

Authors: Abe-Suzuki S, Kurata M, Abe S, Onishi I, Kirimura S, Nashimoto M, Murayama T, Hidaka M, Kitagawa M

Abstract

The bone marrow microenvironment, known as ‘hematopoietic stem cell niche,’ is essential for the survival and maintenance of hematopoietic stem cells. Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell diseases, which eventually result in leukemic transformation (acute myelogenous leukemia with myelodysplasia-related changes, AML-MRC). However, the precise components and functions of the MDS niche remain unclear. Recently, CXCL12-abundant reticular cells were shown to act as a hematopoietic stem cell niche in the murine bone marrow. Using immunohistochemistry, we show here that CXCL12(+) cells were located in the cellular marrow or perivascular area, and were in contact with CD34(+) hematopoietic cells in control and MDS/AML-MRC bone marrow. MDS bone marrow exhibited higher CXCL12(+) cell density than control or AML, not otherwise specified (AML-NOS) bone marrow. Moreover, AML-MRC bone marrow also exhibited higher CXCL12(+) cell density than control bone marrow. CXCL12(+) cell density correlated positively with bone marrow blast ratio in MDS cases. CXCL12 mRNA level was also higher in MDS bone marrow than in control or AML-NOS bone marrow. In vitro coculture analysis revealed that overexpression of CXCL12 in stromal cells upregulated BCL-2 expression of leukemia cell lines. Triple immunostaining revealed that the CD34(+) hematopoietic cells of MDS bone marrow in contact with CXCL12(+) cells were BCL-2-positive and TUNEL-negative. In the bone marrow of MDS cases, CXCL12-high group showed significantly higher Bcl-2(+)/CD34(+) cell ratio and lower apoptotic cell ratio than CXCL12-low group. Moreover, CXCL12-high refractory cytopenia with multilineage dysplasia (RCMD) cases had a greater tendency to progress to refractory anemia with excess blasts (RAEBs) or AML-MRC than CXCL12-low RCMD cases. These results suggest that CXCL12(+) cells constitute the niche for CD34(+) hematopoietic cells, and may be associated with the survival/antiapoptosis of CD34(+) hematopoietic cells and disease progression in MDS. Thus, CXCL12(+) cells may represent a novel MDS therapeutic target.Laboratory Investigation advance online publication, 8 September 2014; doi:10.1038/labinvest.2014.110.

PMID: 25199050 [PubMed - as supplied by publisher]

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Real-Time Analysis of Imatinib- and Dasatinib-Induced Effects on Chronic Myelogenous Leukemia Cell Interaction with Fibronectin.

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Real-Time Analysis of Imatinib- and Dasatinib-Induced Effects on Chronic Myelogenous Leukemia Cell Interaction with Fibronectin.

PLoS One. 2014;9(9):e107367

Authors: Obr A, Röselová P, Grebe?ová D, Kuželová K

Abstract

Attachment of stem leukemic cells to the bone marrow extracellular matrix increases their resistance to chemotherapy and contributes to the disease persistence. In chronic myelogenous leukemia (CML), the activity of the fusion BCR-ABL kinase affects adhesion signaling. Using real-time monitoring of microimpedance, we studied in detail the kinetics of interaction of human CML cells (JURL-MK1, MOLM-7) and of control BCR-ABL-negative leukemia cells (HEL, JURKAT) with fibronectin-coated surface. The effect of two clinically used kinase inhibitors, imatinib (a relatively specific c-ABL inhibitor) and dasatinib (dual ABL/SRC family kinase inhibitor), on cell binding to fibronectin is described. Both imatinib and low-dose (several nM) dasatinib reinforced CML cell interaction with fibronectin while no significant change was induced in BCR-ABL-negative cells. On the other hand, clinically relevant doses of dasatinib (100 nM) had almost no effect in CML cells. The efficiency of the inhibitors in blocking the activity of BCR-ABL and SRC-family kinases was assessed from the extent of phosphorylation at autophosphorylation sites. In both CML cell lines, SRC kinases were found to be transactivated by BCR-ABL. In the intracellular context, EC50 for BCR-ABL inhibition was in subnanomolar range for dasatinib and in submicromolar one for imatinib. EC50 for direct inhibition of LYN kinase was found to be about 20 nM for dasatinib and more than 10 µM for imatinib. Cells pretreated with 100 nM dasatinib were still able to bind to fibronectin and SRC kinases are thus not necessary for the formation of cell-matrix contacts. However, a minimal activity of SRC kinases might be required to mediate the increase in cell adhesivity induced by BCR-ABL inhibition. Indeed, active (autophosphorylated) LYN was found to localize in cell adhesive structures which were visualized using interference reflection microscopy.

PMID: 25198091 [PubMed - as supplied by publisher]

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Chronic myeloid leukemia with an e1a3 BCR-ABL fusion protein: transformation to lymphoid blast crisis.

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Chronic myeloid leukemia with an e1a3 BCR-ABL fusion protein: transformation to lymphoid blast crisis.

Biomark Res. 2014;2:14

Authors: Martinez-Serra J, Del Campo R, Gutierrez A, Antich JL, Ginard M, Durán MA, Bento L, Ros T, Amat JC, Vidal C, Iglesias JF, Orlinska I, Besalduch J

Abstract

Chronic myelogenous leukemia (CML) results from the neoplastic transformation of a hematopoietic stem cell. CML is cytogenetically characterized by the presence of the Philadelphia chromosome (Ph’). Most patients with CML express e13a2 or e14a2 mRNAs that result from a rearrangement of the major breakpoint cluster regions (M-BCR) generating the 210-kDa (p210BCR-ABL) fusion proteins b2a2 or b3a2 respectively. The e1a3 CML-related atypical translocation has been reported with an indolent clinical course, low leukocyte count, long chronic phase even without treatment and good response to therapy. We report the case of a patient initially diagnosed as CML in chronic phase whose cells expressed the e1a3 variant. The patient readily responded to imatinib 400 mg with the achievement of a rapid complete cytogenetic response and the normalization of the blood count values, but after 5 months transformed into lymphoid blast crisis.

PMID: 25197554 [PubMed]

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

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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.

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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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