semaxinib and Leukemia--Myeloid--Acute

The vascularization is a very important part of a structure of each tissue both normal, including bone marrow stroma, and pathologically changed. Neoplastic tissues secure supplying in necessary substances for growth and expansion through regulated by its own cells neovasculation. Key role in multipotential cell's differentiation to endothelial cells plays regulatory system consisted of vascular-epithelial growth factor's family (VEGF B, C, D), receptors VEGFR-1, -2, -3, and system Tie2/angiopoetins. Stimulation and importance of angiogenesis for expansion of neoplastic diseases is a current problem in oncology. It is pointed to importance of neovascularization in pathogenesis of acute and chronic leukemias, lymphomas and multiple myeloma. The knowledge of the importance ofvascularization of neoplastic tissues is availing in therapy (researching of substances inhibiting angiogenesis--semaxinib, SU6668, ZD 6474, thalidomid, cetuximab, gefitinib, interferon-alpha, irradiation and others), in diagnostics as a monitoring of a success of the therapy, and in prognosis. Inhibitors ofangiogenesis are antineoplastic drugs with relatively lower toxicity, and lower risk of drug-resistance than conventional chemotherapy what has the importance especially during prolong administration, so they can be an alternative way of therapeutic process. During qualification for antiangiogenic therapy it is necessary to have a consciousness of its limited efficiency.

Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Angiopoietin-1; Angiopoietin-2; Hematologic Neoplasms; Humans; Indoles; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasm Metastasis; Neovascularization, Pathologic; Oxindoles; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Propionates; Pyrroles; Receptor, TIE-2; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factors

Acute myeloid leukaemia (AML) is characterised by the infiltration of the bone marrow with highly proliferative leukaemic cells that stop to differentiate at different stages of myeloid development and carry survival advantages. Conventionally, AML is treated with aggressive cytotoxic therapy, in eligible patients followed by allogeneic bone marrow transplantation. However, despite this aggressive treatment, many patients relapse and eventually die from the disease. Activating mutations in the coding sequence of the receptor tyrosine kinase Flt3 are found in leukaemic blasts from approximately 30% of AML patients. The mutations have been described to severely alter the signalling properties of this receptor and to have transforming activity in cell-line models and in primary mouse bone marrow. The prognosis of patients harbouring the most common Flt3 mutations tends to be worse than that of comparable patients without the mutations. Thus, Flt3 seems a promising target for therapeutic intervention. Several small molecules that inhibit Flt3 kinase activity are being evaluated for the treatment of AML in clinical trials. This review article discusses the signal transduction and biological function of Flt3 and its mutations in normal and malignant haematopoiesis and recent progress in drug development aiming at the inhibition of Flt3 kinases.

Topics: Animals; Antineoplastic Agents; Carbazoles; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Therapy, Combination; fms-Like Tyrosine Kinase 3; Furans; Humans; Indoles; Leukemia, Myeloid, Acute; Mutation; Protein Kinase Inhibitors; Pyrroles; Signal Transduction; Staurosporine

Flt3 is a tyrosine kinase receptor expressed on hematopoietic cells. Activating mutations of this receptor are encountered in over one-fourth of acute myelogenous leukemia (AML) cases and activate multiple intracellular pathways leading to cell proliferation, inhibition of apoptosis, and blockage of differentiation in leukemic blasts. AML with flt3 mutations has a worse prognosis than AML with normal flt3, at least in younger patients. Several flt3 inhibitors are in various stages of preclinical and clinical development and it is hoped that specific therapies against AML with flt3 mutations will soon be available to the clinician.

Topics: Adult; Animals; Enzyme Inhibitors; fms-Like Tyrosine Kinase 3; Humans; Indoles; Leukemia, Myeloid, Acute; Mice; Middle Aged; Prognosis; Proto-Oncogene Proteins; Pyrroles; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases; Treatment Outcome

Neoangiogenesis has been shown to play an important role in the pathogenesis of acute myeloid leukemia (AML). Autocrine and paracrine secretion of angiogenic and hematopoietic growth factors such as vascular endothelial growth factor (VEGF) and stem cell factor (SCF) in the bone marrow microenvironment may promote proliferation and survival of leukemic blasts. This concept represented the rationale for the initiation of a multicenter phase 2 trial of SU5416, a small molecule inhibitor of phosphorylation of VEGF receptors 1 and 2, c-kit, the SCF receptor, and fms-like tyrosine kinase-3 (FLT3) in patients with advanced AML. Entered into the study were 43 patients with refractory AML or elderly patients not judged medically fit for intensive induction chemotherapy; 42 patients received at least one dose of study drug. Treatment was generally well tolerated, with nausea, headache, and bone pain the most frequent treatment-related side effects. One patient had a morphologic remission (French-American-British [FAB] criteria of complete response without normalization of blood neutrophil and platelet counts) lasting for 2 months. There were 7 patients who achieved a partial response (reduction of blasts by at least 50% in bone marrow and peripheral blood) lasting 1 to 5 months. Patients with AML blasts expressing high levels of VEGF mRNA by quantitative polymerase chain reaction (PCR) had a significantly higher response rate and reduction of bone marrow microvessel density than patients with low VEGF expression consistent with the antiangiogenic effects of SU5416.

Topics: Adult; Aged; Angiogenesis Inhibitors; Bone Marrow; Cell Separation; Enzyme Inhibitors; Female; Flow Cytometry; Humans; Indoles; Leukemia, Myeloid, Acute; Male; Membrane Proteins; Microcirculation; Middle Aged; Mutation; Polymerase Chain Reaction; Pyrroles; Recurrence; Remission Induction; Time Factors; Treatment Outcome; Vascular Endothelial Growth Factor A