Antiangiogenic Therapy in Leukemia

Abstract

Angiogenesis is a fundamental element of the physiological processes of embryogenesis and wound healing. During malignant transformation, dysregulation of angiogenesis leads to the formation of a vascular network of tumor-associated capillaries promoting survival and proliferation of the cancerous cells. Activation, migration, proliferation and differentiation of endothelial cells into mature blood vessels is driven by several cytokines and growth factors, known to be dysregulated in hematological malignancies. Thus, therapeutic interventions designed to eradicate the malignant clone should incorporate modulation of the angiogenic cascade. Antiangiogenic agents which target different components of the neovascularization process are being investigated in various solid tumors known to have increased vascularity. The role of angiogenesis in hematological malignancies, the rationale for the use of angiosuppressive therapy for these entities, and the status of novel antiangiogenic agents in clinical trials are discussed.

Phase II Study of SU5416, a Small Molecule Vascular Endothelial Growth Factor Tyrosine Kinase Receptor Inhibitor, in Patients with Refractory Multiple Myeloma

“…The initial agent investigated in this context was thalidomide, which has both antiangiogenic and immunomodulatory properties (35,36). In all studies reported to date, varying rates and degrees of response to thalidomide have been documented, including in patients who have failed aggressive standard combination cytotoxic and corticosteroid therapy (37)(38)(39)(40).…”

Assessment of Plasma Endostatin Levels in Patients with Acute Myeloblastic and Lymphoblastic Leukemia

“…33,34 It has been shown in several studies that systemic levels of these mediators could be important in the regulation of angiogenesis. 10,35,36 Most of the initial studies in angiogenesis were done on solid tumors. However, there are increasing numbers of studies that demonstrate the importance of angiogenesis in hematologic malignancies.…”

“…[7][8][9] Recently, it has also been recognized that disregulation of angiogenesis constitutes an important step in the development and progression of hematological malignancies and that leukemias may invade and proliferate in the bone marrow and other organs by mechanisms similar to those reported in solid tumors. 10 The interaction of endothelial cells and the marrow microenvironment with hematopoietic progenitors and leukemia cells play a role in the development of the leukemic phenotype by virtue of the secretion of proangiogenic and antiangiogenic cytokins. The blood levels of pro-angiogenic and anti-angiogenic growth factors can be measured and may have prognostic and diagnostic values.…”

“…It has been reported that the blood levels of some proangiogenic factors such as VEGF, bFGF and hepatocyte growth factor (HGF) might be elevated and correlated with unfavorable prognosis in patients with AML and myelodysplastic syndrome (MDS). 10,11 Most studies about the role of angiogenic factors in ALL have been conducted in children, and data are limited in adults. It was reported that elevated VEGF levels are associated with good prognosis and longer survival in a study of the adult patients with ALL, in contrast with the results that have been obtained from children.…”

Novel therapies for myelodysplastic syndromes

“…Based on a number of preclinical investigations that confirmed the pathophyiologic role of angiogenesis in leukemias and MDS, a number of small molecule inhibitors of angiogenic agents and receptors have been developed and have entered clinical trials. 74 Thalidomide. Thalidomide has significant antitumor activity in patients who have hematologic malignancies with increased bone marrow angiogenesis and has been shown to inhibit bFGF and VEGF-induced angiogenesis.…”