Leukemia regression by vascular disruption and anti-angiogenic therapy
- Gerard J. Madlambayan1,
- Amy Meacham1,
- Koji Hosaka2,
- Saad Mir1,
- Marda Jorgensen2,
- Edward W. Scott2,
- Dietmar W. Siemann3, and
- Christopher R. Cogle1,*
- 1 Department of Medicine, Division of Hematology/Oncology, University of Florida, Gainesville, FL, United States;
- 2 Program in Stem Cell Biology and Regenerative Medicine, University of Florida, Gainesville, FL, United States;
- 3 Department of Radiation Oncology, University of Florida, Gainesville, FL, United States
- * Corresponding author; email: c{at}ufl.edu
Abstract
Acute myelogenous leukemias (AML) and endothelial cells depend on each other for survival and proliferation. Monotherapy anti-vascular strategies such as targeting vascular endothelial growth factor (VEGF) has limited efficacy in treating AML. Thus, in search of a multi-target anti-vascular treatment strategy for AML we tested a novel vascular disrupting agent, OXi4503, alone and in combination with the anti-VEGF antibody, bevacizumab. Using xenotransplant animal models, OXi4503 treatment of human AML chloromas led to vascular disruption in leukemia cores that displayed increased leukemia cell apoptosis. However, viable rims of leukemia cells remained and were richly vascular with increased VEGF-A expression. To target this peripheral reactive angiogenesis, bevacizumab was combined with OXi4503 and abrogated viable vascular rims, thereby leading to enhanced leukemia regression. In a systemic model of primary human AML, OXi4503 regressed leukemia engraftment alone and in combination with bevacizumab. Differences in blood vessel density alone could not account for the observed regression, suggesting that OXi4503 also exhibited direct cytotoxic effects on leukemia cells. In vitro analyses confirmed this targeted effect, which was mediated by the production of reactive oxygen species and resulted in apoptosis. Together, these data show that OXi4503 alone is capable of regressing AML by means of a multi-targeted mechanism and that the addition of bevacizumab mitigates reactive angiogenesis.
- Submitted June 29, 2009.
- Accepted May 5, 2010.
- Copyright © 2005 American Society of Hematology
