A Worldwide Support Network For Chronic Myelogenous Leukemia
Posted by rob on July 31, 2011 under Uncategorized | 
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Obesity and the risk of chronic myelogenous leukemia: is this another example of the neoplastic effects of increased body fat?
Leukemia advance online publication, July 22, 2011. doi:10.1038/leu.2011.190
Author: M A Lichtman (Source: Leukemia)
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Authors: Ebada SS, Schulz B, Wray V, Totzke F, Kubbutat MH, Müller WE, Hamacher A, Kassack MU, Lin W, Proksch P
Bioassay-guided fractionation of a methanolic extract of the fungus Arthrinium sp., isolated from the Mediterranean sponge Geodia cydonium, afforded 10 natural products including five new diterpenoids, arthrinins A-D (1-4) and myrocin D (5). In addition, five known compounds were obtained, which included myrocin A (6), norlichexanthone (7), anomalin A (8), decarboxycitrinone (9) and 2,5-dimethyl-7-hydroxychromone (10). The structures of all isolated compounds were unambiguously elucidated based on extensive 1D and 2D NMR and HR-MS analyzes. The absolute configuration of arthrinins A-D (1-4) was established by the convenient Mosher method performed in NMR tubes and by interpr…
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Source: J Clin Oncol
Area: News
This French prospective study evaluated the use of imatinib in children and adolescents with chronic myeloid leukemia (CML) in the chronic phase (CP). Imatinib is used as standard care in adults with this condition, however, few data exist in children. Children age 0 to 18 years with previously untreated Philadelphia (Ph) chromosome positive CML in CP diagnosed within 2 months were eligible for entry. The study protocol permitted prior therapy with hydroxyurea (HU). Between March 2004 and December 2008, 44 patients were enrolled from16 academic hospitals in France. Study participants received imatinib 260 mg/m2 (maximum 400 mg) orally once daily. The primary objective of the study was to determine the progression-free survival (PFS) rate (defined as t…
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Conclusion
Imatinib is effective in children with CML in CP with response rates similar to rates reported in adults. The adverse effects are acceptable, but longer follow-up studies are required to fully assess the long-term impact. (Source: Journal of Clinical Oncology)
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Conclusions Bosutinib 200–600 mg with food was safe and well tolerated. Under fed conditions, bosutinib exposures were linear and dose
proportional, and C
max increased by ~1.5-fold. The t
1/2 supported a once-daily dosing regimen.
Content Type Journal ArticlePages 1-7DOI 10.1007/s00280-011-1688-7Authors
Richat Abbas, Department of Clinical Pharmacology, Pfizer Inc, 500 Arcola Road, Collegeville, PA 19426, USABruce A. Hug, Department of Clinical Pharmacology, Pfizer Inc, 500 Arcola Road, Collegeville, PA 19426, USACathie Leister, Department of Clinical Pharmacology, Pfizer Inc, 500 Arcola Road, Collegeville, PA 19426, USAMyriam El Gaaloul, Department of Clinical Pharmacology, Pfizer Global Research and Development, Paris, FranceStephan Chalon, Department of …
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Inhibition of protein tyrosine phosphatase 1B (PTP1B) mediates ubiquitination and degradation of Bcr-Abl.
J Biol Chem. 2011 Jul 27;
Authors: Alvira D, Naughton R, Bhatt L, Tedesco S, Landry WD, Cotter TG
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-Abl, a chimeric protein with deregulated tyrosine kinase activity. The protein tyrosine phosphatase 1B (PTP1B) is up-regulated in Bcr-Abl expressing cells suggesting a regulatory link between the two proteins. To investigate the interplay between these two proteins we inhibited the activity of PTP1B in Bcr-Abl expressing TonB.210 cells by either pharmacological or siRNA means and examined effects of such inhibition on Bcr-Abl expression and function. Herein we describe a novel mechanism by which the phosphatase activity of PTP1B is required for Bcr-abl protein stability. Inhibition of PTP1B elicits tyrosine phosphorylation of Bcr-Abl that triggers the degradation of Bcr-Abl through ubiquitination via the lysosomal pathway. The degradation of Bcr-Abl consequently inhibits tyrosine phosphorylation of Bcr- Abl substrates and the downstream production of intracellular reactive oxygen species (ROS). Furthermore, PTP1B inhibition reduces cell viability and the IC50 of the Bcr-Abl inhibitor imatinib mesylate. Degradation of Bcr-Abl via PTP1B inhibition is also observed in human CML cell lines K562 and LAMA-84. These results suggest that inhibition of PTP1B may be a useful strategy to explore in the development of novel therapeutic agents for the treatment of CML, particularly since host drugs currently used in CML such as imatinib focus on inhibiting the kinase activity of Bcr-Abl.
PMID: 21795709 [PubMed - as supplied by publisher]
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[A case of imatinib mesylate-induced pneumonitis based on the detection of epithelioid granulomas by video-assisted thoracoscopic surgery biopsy in a patient with chronic myeloid leukemia].
Nihon Kokyuki Gakkai Zasshi. 2011 Jun;49(6):465-71
Authors: Koide T, Saraya T, Nakamoto K, Nakajima A, Ishii H, Fujiwara M, Shibata H, Oka T, Goya T, Goto H
A 79-year-old man with chronic myeloid leukemia was referred to our department because of dry cough and low-grade fever, 272 days after commencing imatinib mesylate (Gleevec). High resolution computed tomography (HRCT) showed tiny scattered centrilobular nodules and ground-glass opacities throughout both lung fields, suggesting drug-induced pneumonitis. A thoracic video-assisted thoracoscopic surgery (VATS) biopsy specimen from the centrilobular nodules in the right upper lobe demonstrated patchy distribution of epithelioid cell granulomas and intra-alveolar organization. Most of those lesions were predominantly located in the alveolar spaces, which implicated non-transbronchial distribution. Following drug cessation alone, the patient’s general condition and radiological abnormalities improved.
PMID: 21735750 [PubMed - indexed for MEDLINE]
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Practical advice for determining the role of BCR-ABL mutations in guiding tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia.
Cancer. 2011 May 1;117(9):1800-11
Authors: Jabbour E, Branford S, Saglio G, Jones D, Cortes JE, Kantarjian HM
Data demonstrating the superiority of nilotinib over imatinib in the frontline treatment of chronic myeloid leukemia (CML) and ongoing studies with dasatinib and bosutinib are rapidly changing the treatment landscape for CML. In this review, the authors discuss currently available therapies for CML, focusing on mechanisms of resistance to imatinib and treatment strategies to overcome resistance. Relevant articles were identified through searches of PubMed and abstracts from international hematology/oncology congresses. Additional information sources were identified from the bibliographies of these references and from the authors’ own libraries and expertise. In vitro 50% inhibitory concentration (IC(50) ) data alone are not sufficient to guide the choice of a tyrosine kinase inhibitor (TKI) in the presence of a mutant breakpoint cluster region-v-abl Abelson murine leukemia viral oncogene homolog (BCR-ABL) clone, because there is a lack of data regarding how well such IC(50) values correlate with clinical response. A small subset of BCR-ABL mutant clones have been associated with impaired responses to second-generation TKIs (tyrosine to histidine mutation at codon 253 [Y253H], glutamic acid to lysine or valine mutation at codon 255 [E255K/V], and phenylalanine to cysteine or valine mutation at codon 359 [F359C/V] for nilotinib; valine to leucine mutation at codon 299 [V299L] and F317L for dasatinib); neither nilotinib nor dasatinib is active against the threonine to isoleucine mutation at codon 315 (T315I). For each second-generation TKI, the detection of 1 of a small subset of mutations at the time of resistance may be helpful in the selection of second-line therapy. For the majority of patients, comorbidities and drug safety profiles should be the basis for choosing a second-line agent. Clinical trial data from an evaluation of the response of specific mutant BCR-ABL clones to TKIs is needed to establish the role of mutation testing in the management of CML.
PMID: 21509757 [PubMed - indexed for MEDLINE]
