Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Philadelphia (Ph) chromosome was the first consistent chromosome abnormality identified in cancer. It is found in 90% of patients with chronic myeloid leukaemia (CML) and in a subset of patients with acute lymphoblastic leukaemia. The effectiveness of the Bcr-Abl kinase inhibitor imatinib in these conditions reduces with advancing disease and/or the development of resistance to imatinib. AMN-107 inhibited the proliferation of haematopoietic cells expressing the mutants in Ph+ CML and acute lymphoblastic leukaemia with concentrations causing 50% inhibition of approximately 12 nM, making it more potent than imatinib. AMN-107 was also effective against several imatinib-resistant Bcr-Abl mutants, but not T3151. In mice transduced with Bcr-Abl, AMN-107 reduced mortality and tumour burden. In mice transduced with the E255V imatinib-resistant mutant of Bcr-Abl, AMN-107 delayed the onset of leukaemia. As AMN-107 is more potent and more selective for Bcr-Abl than imatinib, it may represent a step forward in the treatment of CML, but further animal (and then clinical) studies are needed to test this.
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PMID:Is AMN-107 a step forward from imatinib in the treatment of chronic myeloid leukaemia? 1605 Jul 98

Imatinib mesylate (Gleevec) has dramatically changed the strategy of chronic myeloid leukemia (CML) therapy. However, resistance is often reported in advanced-stage CML patients. Several novel tyrosine kinase inhibitors which have been developed to override imatinib resistance mechanism due to point mutations within the Abl kinase domain. Quite recently we successfully developed the novel Bcr-Abl/Lyn dual inhibitor INNO-406 (NS-187) which shows unique profile to overcome this resistance. Inhibitors of Abl tyrosine kinase are divided into two groups, ATP-competitive and non-competitive inhibitors. ATP-competitive inhibitors are further fall into two subclasses, the Src/Abl inhibitors and 2-phenylaminopyrimidin-based compounds. Dasatinib (BMS-354825, Sprycel) is classified as Src/Ablinhibitors while nilotinib (AMN 107) and INNO-406 (NS-187) belong to the latter. Among them, clinical studies on dasatinib and AMN 107 had started earlier than the others and favorable results are accumulating. We have performed basic and preclinical studies of INNO-406 (NS-187) in Japan, and then its clinical trials have been commenced firstly in the United States from July, 2006. The ultimate goal of clinical development is to bring the novel therapeutics with regulatory safety and efficacy to the clinical settings as soon as possible. Considerations important for the innovation of clinical trials for anti-cancer drugs in Japan are discussed.
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PMID:[Innovation of clinical trials for anti-cancer drugs in Japan--proposals from academia with special reference to the development of novel Bcr-Abl/Lyn tyrosine kinase inhibitor INNO-406 (NS-187) for imatinib-resistant chronic myelogenous leukemia]. 1730 49

Nilotinib (AMN-107, Tasigna) is a small-molecule inhibitor of BCR/ABL, approved for chronic myelogenous leukemia. We developed and validated, according to FDA-guidelines, an LC-MS assay for sensitive, accurate and precise quantitation of nilotinib in 0.2 mL human plasma or serum. After acetonitrile protein precipitation, separation is achieved with a hydro-Synergi column and a 0.1% formic acid in methanol/water-gradient. Detection uses electrospray, positive-mode ionization mass spectrometry. Between 5 (LLOQ) and 5000 ng/mL, accuracy (92.1-109.5%), intra-assay precision (2.5-7.8%), and inter-assay precision (0-5.6%)) were within FDA limits. We demonstrated the suitability of this assay by quantitating plasma concentrations of nilotinib in a healthy volunteer after oral administration of 400 mg nilotinib.
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PMID:A high-performance liquid chromatography-mass spectrometry assay for quantitation of the tyrosine kinase inhibitor nilotinib in human plasma and serum. 1949 8

The patient first noticed spasticity and weakness in his legs. He was diagnosed with chronic myelogenous leukemia (CML); the symptoms were attributed to neuropathy associated with CML. By treatment with dasatinib, he achieved complete hematological remission, but his difficulty in walking was not improved. His neurological symptom worsened together with an increase in body temperature and then disappeared together with a normalized body temperature, which may be attributed to the Uhthoff's phenomenon often observed in multiple sclerosis. He later developed acute fever, vomiting and a high adrenocorticotropic hormone (ACTH) level, which was diagnosed as adrenal insufficiency. Eventually, he was diagnosed with a milder form of adrenoleukodystrophy (ALD), adrenomyeloneuropathy (AMN) by increased levels of Very Long Chain Fatty Acids (VLCFAs) and genetic testing of the ATP binding cassette subfamily D member 1 (ABCD1) gene. A missense mutation (c.521A>C, p.Tyr174Ser), previously reported to induce severe cerebral ALD, was detected in exon1. Thus, clinical manifestation of ALD is determined by interaction between the primary ABCD1 mutation and modifying genetic and environmental factors. Physicians should be aware of the differing symptoms of AMN and determine the level of VLCFAs in patients having primary adrenal insufficiency, especially those complicated with neurological dysfunction. This is the first report of an AMN patient complicated with CML.
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PMID:A first case of adrenomyeloneuropathy with mutation Y174S of the adrenoleukodystrophy gene. 2845 43