semaxinib and Multiple-Myeloma

Research on the formation of new blood vessels (angiogenesis) in general and vascular endothelial growth factor (VEGF) in particular is a major focus in biomedicine and has led to the clinical approval of the monoclonal anti- VEGF antibody bevazicumab; and the second-generation multitargeted receptor kinase inhibitors (RTKIs) sorafenib, sunitinib, and pazopanib. Although these agents show significant preclinical and clinical anti-cancer activity, they prolong overall survival of cancer patients for only months, followed by a restoration of tumor growth and progression. Therefore, there is a clear need to increase our understanding of tumor angiogenesis and the development of resistance. In this review we discuss up-to-date knowledge on mechanisms of tumor angiogenesis, and summarize preclinical and clinical data on existing and potential future anti-angiogenic agents and treatment strategies for Multiple Myeloma (MM) and other hematologic and solid malignancies.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Benzenesulfonates; Hematologic Neoplasms; Humans; Indoles; Multiple Myeloma; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Phthalazines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sorafenib; Sunitinib; Thalidomide; Vascular Endothelial Growth Factor A; Wnt Signaling Pathway

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

Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are of adverse prognostic significance in patients with multiple myeloma (MM). VEGF, a soluble circulating angiogenic molecule, acts via receptor tyrosine kinases, including VEGF receptor 2. SU5416 is a small molecule VEGF receptor 2 inhibitor.. Adult patients with advanced MM were entered on a multicenter phase II study.. Twenty-seven patients (median age 69, range 39-79), median 4 (0-10) lines of prior therapy, 14 with prior thalidomide therapy, received SU5416 at 145 mg/m(2) twice weekly i.v. for a median of two 4-week cycles (range 0.2-9). Grade 3/4 toxicities were rarely observed; the most frequent was thrombocytopenia (12%). Mild-to-moderate toxicities included nausea (63%), headache (56%), diarrhea, vomiting (both 37%), and fatigue (33%). There were three thromboembolic episodes and five cases of new onset hypertension. Two (7%) patients did not complete the first 4-week cycle of therapy because of adverse events (pneumonia and headache). There were no objective responses. Four patients had disease stabilization for >/==" BORDER="0">4 months. A decrease in median VEGF plasma levels was observed in patients with stable disease (n = 7) compared with patients with progressive disease (n = 5). Overall median survival was 42 weeks (range 3-92+).. Although SU5416 had minimal clinical activity, signs of biological activity (decrease in plasma VEGF levels) suggest that angiogenic modulation may be of value in patients with MM.

Topics: Adult; Aged; Angiogenesis Inhibitors; Biomarkers, Tumor; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Humans; Indoles; Male; Middle Aged; Multiple Myeloma; Neovascularization, Pathologic; Protein-Tyrosine Kinases; Pyrroles; Remission Induction; Salvage Therapy; Survival Rate; Thalidomide; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2