Tyrosine kinase inhibitors Philadelphia chromosome

Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia after ima-tinib treatment and for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and 6 hours (Tmax) following oral administration. Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. CYP3A4 was the primary enzyme responsible for the formation of the active metabolite. The overall mean terminal half-life of dasatinib is 3-5 hours. Adverse events included mild to moderate diarrhea, peripheral edema, and headache. Neutropenia and myelosuppression were common toxic effects. 

Hofmann WK, de Vos S, Elashoff D et al. Relation between resistanee of Philadelphia-chromosome-positive acute lymphoblastie leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles a gene-expression study. Lancer 2002 359 481 86. 

Imatinib. Chronic myelogenous leukemia (CML) results from a genetic defect in the hematopoietic stem cells of the bone marrow. Nearly all CML patients possess the Philadelphia chromosome. It results from translocation between chromosomes 9 and 22 of the c-abl protooncogene, leading to the hybrid bcr-abl fusion gene on chromosome 22. The recombinant gene encodes a tyrosine kinase mutant with unregulated (constitutive), enhanced activity that promotes cell proliferation. Imatinib is a tyrosine kinase inhibitor that specifically affects this mutant but also interacts with some other kinases. It can be used orally in Philadelphia chromo-some-positive CML. 

Designer molecular therapy. A tyrosine kinase inhibitor, imatinib, is specifically designed to block the dysregulated t5n"osine kinase hyperactivity produced by the Philadelphia chromosome that is specific for chronic granulocytic leukaemia clinical trials support its efficacy in this disease. 

Imatinib mesylate is a new tyrosine kinase inhibitor designed for the treatment of CML. It inhibits the Bcr-AbI tyrosine kinase leading to inhibition of proliferation and induction of apoptosis in Bcr-Abl-positive cells. Imatinib is indicated for treatment of CML in blast crisis, accelerated phase, or chronic phase in patients who have failed interferon therapy. Response rates have been evaluated in terms of hematologic and cytogenetic (decrease or disappearance of Philadelphia chromosome) responses. 

Imatinib mesylate was the first tyrosine kinase inhibitor to be approved for treatment of cancer (see Table 124—18). It inhibits deregulated bcr-abl tyrosine kinase, the molecular abnormality in patients with chronic myelogenous leukemia that results from the characteristic Philadelphia chromosome translocation. The deregulated tyrosine kinase constantly drives leukemic cell proliferation. Imatinib inhibits cell proliferation and induces apoptosis in the Philadelphia chromosome-positive cells. It is relatively, but not completely, selective for these cells. °°... 

Imatinib is a protein-tyrosine-kinase inhibitor. Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome-positive (Ph-r) chronic myeloid leukemia (CML). Imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells and BCR-ABL positive leukemia lines derived from CML patients in blast crisis. It also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. It is indicated in the treatment of newly diagnosed adult patients with Ph-t CML in chronic phase patients with Ph-t CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha treatment children with Ph-t chronic phase CML whose disease has recurred after stem cell transplant or who are resistant to interferon-alpha therapy and treatment of gastrointestinal stromal tumors (GIST). 

Inhibition of hematopoietic growth factors Imatinib (Glivec ) is applied to treat chronic myeloid leukemia in Philadelphia-chromosome positive patients. In these patients, translocation of parts of chromosomes 9 and 22 results in the expression of a fusion protein with increased tyrosine kinase activity, called Bcr-Abl. Imatinib is a small Mw inhibitor selective for the tyrosine kinase activity of Bcr-Abl. Thereby, it inhibits the Bcr-Abl induced cell cycle progression and the uncontrolled proliferation of tumor cells. 

The proportion of ALL in patients older than age 60 years constitutes between 16% and 31% of all adult leukemias. Treatment of adults largely has followed the conventional chemotherapeutic regimes used in childhood ALL. However, the intensification regimens common in childhood are not suitable for this population because of their associated toxic-ities in older patients. The adverse prognostic factor, the Philadelphia chromosome, occurs in 15% to 30% of adults and thus is more common in the over 60 age group.17 Based on the experience achieved in CML, the use of imatinib, a potent inhibitor of the Ph+-associated BCR-ABL tyrosine kinase, is becoming a common practice for these older adults. Results show that the combination of imatinib with conventional chemotherapy has improved remission rates compared with the use of conventional chemotherapy alone,... 

Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capde-ville R, Talpaz M. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome N. Engl J Med 2001 344 1084-1086. 

Imatinib (STI571) is an inhibitor of the tyrosine kinase domain of the Bcr-Abl oncoprotein and prevents the phosphorylation of the kinase substrate by ATP. It is indicated for the treatment of chronic myelogenous leukemia (CML), a pluripotent hematopoietic stem cell disorder characterized by the t(9 22) Philadelphia chromosomal translocation. This translocation results in the Bcr-Abl fusion protein, the causative agent in CML, and is present in up to 95% of patients with this disease. This agent inhibits other activated receptor tyrosine kinases for platelet-derived growth factor receptor (PDGFR), stem cell factor (SCF), and c-kit. 

The prototype molecularly targeted therapeutic agent is imatinib, an inhibitor of the Bcr-Abl tyrosine kinase. This oncogenic kinase is produced by translocation of the Bcr locus on chromosome 9 to the c-Abl tyrosine kinase on chromosome 11, termed the Philadelphia chromosome because of its discovery in 1960 at the University of Pennsylvania School of Medicine by Peter Nowell and David Hungerford from the Institute for Cancer Research [9]. It was later demonstrated in 1973 by Janet Rowley that the Philadelphia translocation was responsible for a specific form of leukemia, chronic myelogenous leukemia (CML) [10], In 2001, imatinib was approved for treatment of CML patients, and produced remarkable results with more than 92% patients achieving 14-month progression-free survival on imatinib as a monotherapy. 

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