Leukemia regression by vascular disruption and antiangiogenic therapy.
Acute myelogenous leukemias (AMLs) and endothelial cells depend on each other for survival and proliferation. Monotherapy antivascular strategies such as targeting vascular endothelial growth factor (VEGF) has limited efficacy in treating AML. Thus, in search of a multitarget antivascular 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 a multitargeted mechanism and that the addition of bevacizumab mitigates reactive angiogenesis.
Madlambayan
Gerard J
GJ
Department of Medicine, University of Florida, Gainesville, USA.
Meacham
Amy M
AM
Hosaka
Koji
K
Mir
Saad
S
Jorgensen
Marda
M
Scott
Edward W
EW
Siemann
Dietmar W
DW
Cogle
Christopher R
CR
D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis; D000068258:Bevacizumab; D015153:Blotting, Western; D049109:Cell Proliferation; D011756:Diphosphates / Q000627:therapeutic use*; D006801:Humans; D007124:Immunoenzyme Techniques; D053631:Interleukin Receptor Common gamma Subunit / Q000502:physiology; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012074:Remission Induction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023981:Sarcoma, Myeloid / Q000473:pathology / Q000517:prevention & control*; D013267:Stilbenes / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D011756:Diphosphates; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; C465018:Oxi 4503; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013267:Stilbenes; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab
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