semaxinib and vatalanib

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 acute myeloid leukemias (AML) are often fatal disorders with a range of clinical, morphologic, cytogenetic, and molecular features and a consequent need for a diverse array of therapies. This need for tailored therapy for subsets of patients with AML is exemplified in those with acute promyelocytic leukemia, the subject of a separate article in this issue (Tallman and Nabhan). Unfortunately, we tend to examine novel agents in patients with very advanced disease, in which prior therapies have inevitably altered the tumor. Of a myriad of possible exciting novel agents, a few, including PS-341, Genasense (Genta, Berkeley Heights, NJ), decitabine, 5-azacytidine, clofarabine, and troxacitabine, are briefly reviewed with an emphasis on their mechanisms of action from a perspective that suggests possible synergistic therapeutic interventions. With the growing appreciation of the pivotal role of angiogenesis in AML, angiogenesis modulators are a good example of a core class of drugs upon which future noncytotoxic combinations may be built. Those agents targeting vascular endothelial growth factor are also briefly reviewed.

Topics: Acute Disease; Adenine Nucleotides; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Arabinonucleosides; Azacitidine; Bevacizumab; Boronic Acids; Bortezomib; Clofarabine; Cytosine; Decitabine; Dioxolanes; Humans; Indoles; Leukemia, Myeloid; Phthalazines; Pyrazines; Pyridines; Pyrroles; Thionucleotides

The inhibitors of VEGF-mediated signaling continue to wind their way through extensive preclinical and clinical development paths. Whereas the first phase III trial did not meet its endpoints, one hopes that the others will. As we learn more about the VEGF pathways in the laboratory and the clinic, we can interpret with greater certainty what role these drugs or their successors will have in the treatment of human cancers.

Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Clinical Trials as Topic; Colorectal Neoplasms; Drug Design; Drug Screening Assays, Antitumor; Endothelial Growth Factors; Enzyme Inhibitors; Humans; Indoles; Intercellular Signaling Peptides and Proteins; Lymphokines; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Phthalazines; Piperidines; Pyridines; Pyrroles; Quinazolines; Recombinant Proteins; RNA, Catalytic; Treatment Failure; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors

The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor induced angiogenesis. VEGF receptors, the tyrosine kinases Flt-1 and KDR, are expressed on vascular endothelial cells and initiate angiogenesis upon activation by VEGF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit Flt-1 and KDR with IC(50) values < 0.1 microM. CGP 79787D also blocks the VEGF-induced receptor autophosphorylation in CHO cells ectopically expressing the KDR receptor (ED(50) = 34 nM). Modification of the 1-anilino moiety afforded derivatives with higher selectivity for the VEGF receptor tyrosine kinases Flt-1 and KDR compared to the related receptor tyrosine kinases PDGF-R and c-Kit. Since these 1-anilino-(4-pyridylmethyl)phthalazines are orally well absorbed, these compounds qualify for further profiling and as candidates for clinical evaluation.

Topics: Administration, Oral; Angiogenesis Inhibitors; Aniline Compounds; Animals; Biological Availability; Cell Line; CHO Cells; Cricetinae; Enzyme Inhibitors; Humans; Mice; Models, Molecular; Neoplasms; Neovascularization, Pathologic; Phosphorylation; Phthalazines; Proto-Oncogene Proteins; Pyridines; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Structure-Activity Relationship; Transfection; Vascular Endothelial Growth Factor Receptor-1