Antitumor effect of the vascular-disrupting agent ZD6126 in a murine renal cell carcinoma model

Abstract

Abstract. ZD6126 is a vascular-disrupting agent that affects the endothelial tubulin cytoskeleton causing selective occlusion of tumor vasculature and extensive tumor cell necrosis. The present study evaluated the antitumor and antivascular activities of ZD6126 in the clinically relevant murine renal cell carcinoma (RENCA) model and also evaluated biological response to therapy using color Doppler imaging as biomarker. Mice were implanted with RENCA tumor cells (day 0) and established tumors were treated with ZD6126 (100 mg/kg i.p.) or vehicle with repeated intermittent doses on day 10, 14 and 18. ZD6126 treatment led to a significant reduction in tumor size and was associated with extensive tumor necrosis and a reduction in tumor blood flow versus controls. MVD increased with intermittent treatment (day 10, 14 and 18). In an additional study, animals were treated at day 19 and quantitative three-dimensional microvascular corrosion casting was performed to enable detailed assessment of the tumor vascular architecture. Corrosion casting showed that tumor vessel architecture is affected by treatment, whereas pre-existing vessels in control tissues are practically not affected. Inter-vessel and inter-branch distances as well as vessel diameters are influenced by treatment. In conclusion, ZD6126 showed potent antitumor efficacy in the RENCA model and our data suggest that decrease in tumor blood flow may be a useful surrogate marker of treatment effect.

Demonstrating Tumor Vascular Disrupting Activity of the Small-Molecule Dihydronaphthalene Tubulin-Binding Agent OXi6196 as a Potential Therapeutic for Cancer Treatment

“…However, some viable tumor regions remained, primarily as a thin band around the tumor periphery. These observations coincide with similar studies of previous VDAs such as ZD6126 [ 65 ] and DMXAA [ 54 ] in RENCA cells and CA4P or CA1P (OXi4503) in Caki-1 kidney tumors [ 76 ]. Both the tumor growth delay studies and histology suggest that a combined treatment will be required to achieve complete tumor control, as investigated for other VDAs previously [ 3 , 18 , 77 ].…”

“…Tumors are well vascularized and perfused and we found maximum BLI intensity within about 5 min ( Figure 7 ), which is considerably faster than for many tumor types ( Figure 5 and Figure S5 ) and various reports in the literature [ 18 , 33 , 63 , 64 ]. RENCA has previously been investigated with respect to the VDAs DMXAA [ 54 ], ZD6126 [ 65 ], and BNC-105P [ 44 ], each of which entered clinical trials, as well as recent novel molecules OXi8007 [ 18 ] and KGP265 [ 33 ]. We found similar efficacy in both the orthotopic MDA-MB-231-luc and RENCA-luc tumors with about 60% loss of BLI signal following 15 mg/kg OXi6197.…”

Biomarkers in Tumor Angiogenesis and Anti-Angiogenic Therapy

“…ZD6126 treatment led to a significant reduction in tumor size and was associated with extensive tumor necrosis and a reduction in tumor blood flow measured by Doppler imaging ultrasound technique [78]. …”

Contrast enhanced ultrasound imaging can predict vascular-targeted photodynamic therapy induced tumor necrosis in small animals

“…We hypothesized that contrast-enhanced ultrasound (CEUS) may be used to guide laser fiber placement, monitor VTP mediated changes to tumor vasculature, and predict outcomes [3,4]. The high compressibility and resonance properties of gas-filled microbubbles makes them useful intravascular ultrasound contrast agents [5].…”