Anti-Vascular and Anti-Tumor Effects of the Vascular Disrupting Agent ASA404 (DMXAA) in Human Acute Leukemia Xenograft Models

Abstract 4293

Acute leukemia growth and expansion within the marrow microenvironment is linked to increased vascularization. Vascular delivery of chemotherapy drugs within the marrow space may also be an important mediator of anti-leukemic activity. We examined the effects of a tumor -vascular disrupting agent (tumor-VDA), ASA404 (DMXAA; Vadimezan), against human acute leukemia alone and in combination with anthracycline therapy. Exposure of human acute leukemia cells (HEL, Raji) to ASA404 (200–1000 mM) in vitro for up to 72 hours resulted in no evidence of direct cytotoxicity. However, contrast-enhanced magnetic resonance imaging (CE-MRI) performed in mice bearing subcutaneous HEL xenografts revealed an early increase in vascular permeability 4 hours after treatment with a single dose of ASA404 (25 mg/kg). This was followed by significant vascular disruption at 24 hours after therapy as determined by tumor immunohistochemistry. In systemic leukemia xenograft models established with luciferase-transfected HEL and Raji cells, continuous ASA404 treatment (20 mg/kg twice weekly) slowed overall systemic leukemia disease progression (as determined by whole animal bioluminescent imaging) in association with marked marrow vessel dilation, loss of vascular patency, and marked erythrocyte extravasation within the marrow microenvironment. These effects were accompanied by 20–30-fold elevations of circulating systemic TNF-alpha levels in ASA404 versus vehicle treated animals. Combining in vivo ASA404 treatment with anti-human VEGF antibody (bevacizumab) therapy further inhibited leukemia growth as compared with vehicle- or single-agent treated controls. However, concomitant administration of ASA404 with doxorubicin chemotherapy did not improve anti-leukemia effects and was in fact less effective than single agent therapy. In summary, our results demonstrate that ASA404 therapy is capable of mediating in vivo anti-tumor, anti-vascular and immunomodulatory effects in human acute leukemia models. Further strategies to modulate the marrow environment by combining a vascular disrupting agent with other biological agents for acute leukemia therapy may be warranted. However, given the time-dependent effects of VDAs such as ASA404 on tumor vascular function, combining VDAs with chemotherapy is likely to require further optimization of sequence and schedule of administration to ensure adequate marrow drug delivery and maximal therapeutic efficacy in hematological malignancy.