Combretastatin family member OXI4503 induces tumor vascular collapse through the induction of endothelial apoptosis

Abstract

The mechanism of tumor cell killing by OXI4503 was investigated by studying vascular functional and morphological changes post drug administration. SCID mice bearing MHEC5-T hemangioendothelioma were given a single dose of OXI4503 at 100 mg/kg. Tumor blood flow, measured by microsphere fluorescence, was reduced by 50% at 1 hr, and reached a maximum level 6 -24 hr post drug treatment. Tumor vascular permeability, measured by Evan's blue and hemoglobin, increased significantly from 3 hr and peaked at 18 hr. The elevated tumor vessel permeability was accompanied by an increase in vascular endothelial growth factor (VEGF) from 1 hr post drug treatment. Immunohistochemical staining for CD31 and laminin showed that tumor blood vessels were affected as early as 3 hr but more prominent from 6 hr. From 12 hr, the vessel structure was completely destroyed. Histopathological and double immunohistochemical staining showed morphological change and induction of apoptosis in endothelial cells at 1-3 hr, followed by tumor cell necrosis from 6 -72 hr. There were no statistically significant changes of Evan's blue and hemoglobin contents in liver tissue over the time course. These results suggest that OXI4503 selectively targets tumor blood vessels, and induces blood flow shutdown while it enhances tumor blood vessel permeability. The early induction of endothelial cell apoptosis leads to functional changes of tumor blood vessels and finally to the collapse of tumor vasculature, resulting in massive tumor cell necrosis. The time course of the tumor vascular response observed with OXI4503 treatment supports this drug for development as a stand alone therapy, and also lends support for the use of the drug in combination with other cancer therapies.

Nitric Oxide Synthase Inhibition Enhances the Tumor Vascular-Damaging Effects of Combretastatin A-4 3-O-Phosphate at Clinically Relevant Doses

“…6), this suggests that NOS inhibition is particularly effective in interacting with the downstream consequences of CA-4-P treatment. Several studies have shown that CA-4-P and related compounds induce increased tumor expression of hypoxia inducible factor-1α and angiogenic growth factors (44)(45)(46), as well as mobilizing endothelial progenitor cells from bone marrow (47). Others have shown that the combination of VDAs with antiangiogenic agents are particularly effective (48).…”

Tubulin-interactive stilbene derivatives as anticancer agents

“…Several CA-4 derivatives were described and patented as small molecule VDAs [42], including AVE 8062 and Oxi-4503 (Fig. 4), which demonstrate strong anti-tumor effects due to their vasculature-disrupting activity [90,91]. Ombrabulin enhances the efficacy of standard therapies (radiation plus cisplatin and radiation plus cetuximab) in head and neck squamous cell carcinoma (HNSCC) xenograft models.…”

In vivo functional differences in microvascular response of 4T1 and Caki-1 tumors after treatment with OXi4503

“…OXi4503, a Combretastatin family member, is a tubulin binding drug (27,28) and currently considered among the most potent VDAs (13,29). In this study, we employed spectral imaging of window chamber tumors to investigate the realtime VDA-induced modulation in microvessel structure and function of two different tumor types during multiple serial treatments with OXi4503.…”

“…Combretastatins, initially derived from the South African tree Combretum caffrum, represent a class of potent tubulin binding agents with significant vascular disrupting activity (5,8). Lead agents Combretastatin A4-P (CA4-P) and OXi4503 (CA1-P) have been shown to result in time-dependent decreases in tumor perfusion, increased tumor vascular permeability, and significant tumor vascular damage in a wide variety of preclinical tumor models (8,(11)(12)(13). In the clinic, these agents have now entered Phase II/III evaluation (14,15).…”

“…Hence, several different techniques are used for the in vivo assessment of VDA-induced functional and morphological changes in murine and human tumor vasculature. For example, Sheng et al used microsphere fluorescence to assess in vivo tumor blood flow in murine flank tumors after OXi4503 treatment (13). Other techniques such as magnetic resonance imaging and positron emission tomo- ONCOLOGY REPORTS 23: 685-692, 2010 …”