Functional Characteristics of BcrAbl Fig 2
Abl also referred to as Abl-1 , the human homologue of the Abelson murine leukemia virus, is a tyrosine kinase involved in multiple cellular processes, including DNA repair, integrin signaling, cell cycle regulation, and signal transduction from cell surface receptors 11 . ABL knockout mice exhibit increased neonatal lethality and suffer from a number of defects, including skeletal malformations, immune dysfunction as well as an ill-defined wasting syndrome 12,13 . Apart from the FIGURE 1...
International Randomized Study Of Interferon Versus Sti571 Study
The International Randomized Study of Interferon versus STI571 IRIS study established the superiority of 400 mg of imatinib daily over interferon and low dose cyto-sine arabinoside LDAC in a prospective randomized study of 1106 chronic phase patients 39 . The rates of hematologic and cytogenetic responses were higher amongst patients with newly diagnosed chronic phase CML treated with imatinib compared with those who were treated with interferon plus cytarabine. After 12 months of treatment,...
True Chronic Myeloid LeukemiaSpecific Antigen Vaccines
The BCR-ABL-derived p210 protein and particularly the alternative b3a2 or b2a2 peptide epitope at its fusion point is the most obvious CML-specific target, and thus was first explored for a vaccine strategy. p210 is exclusive to the CML clone, and the sequences of amino acids contained in the b3a2 and b2a2 junctional regions represent unique tumor-specific determinants, which can be exploited for an immunological attack against the tumor cell 11 . Recent data support the hypothesis that...
Incidence Of Imatinib Resistance
Primary hematologic resistance in early chronic phase CML is rare lt 5 . The frequency of secondary resistance in early chronic phase CML is also low. According to the international IRIS study group with a followup of 54 month, approximately 4 of patients per year in the imatinib arm had a progression event 14 . Only 1 to 2 of the patients per year progressed to accelerated phase or blast phase CML 14 . Similar percentages of patients per year lost a previously achieved hematologic or...
References Dqc
1. Nowell P, Hungerford, D. A minute chromosome in human chronic granulocytic leukemia. Science 1960 132 1497. 2. Rowley J. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973 243 290 - 293. 3. Druker B, Guilhot F, O'Brien, S, et al. Long-term benefits of imatinib IM for patients newly diagnosed with chronic myelogenous leukemia in chronic phase CML-CP The 5-year update from the IRIS study. Proc Am Soc...
Preclinical Development Of Dasatinib
A series of substituted 2- aminopyridyl - and initially developed as immunosuppressant drugs, were identified as potent dual Src and Abl kinase inhibitors 13 . Dasatinib BMS-354825, Sprycel , thiazole-5-carboxamide was selected for further in vivo studies on the basis of its modest plasma protein binding and sustained blood levels in four-hour exposure studies Fig. 1 13 . The three-dimensional crystal structure of dasatinib complexed with the Abl kinase domain revealed the presence of two...
In Vitro Studies
Results from in vitro studies have demonstrated that nilotinib is more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity in cell lines and that it is at least 10- to 30-fold more potent than imatinib in inhibiting proliferation of Bcr-Abl-expressing cells. Inhibition of cell growth by nilotinib was associated with induction of apoptosis, but it did not decrease the formation of normal human myeloid and erythroid progenitor cells at concentrations lt 100 mm 15 . Nilotinib...