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Updated: Aug 14, 2026
Intravital Microscopy of Tumor-associated Vasculature Using Advanced Dorsal Skinfold Window Chambers on Transgenic Fluorescent Mice
Published on: January 19, 2018
Antitumor activity of the novel vascular targeting agent ZD6126 in a panel of tumor models
David C Blakey1, F Russell Westwood, Mike Walker
1Cancer and Infection Bioscience Department, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. david.blakey@astrazeneca.com
Purpose:
The purpose of this study was to examine the antitumor effects of the novel vascular targeting agent ZD6126 and to use histology, CD31 immunohistochemistry, and electron microscopy to gain an insight into the mechanism of action of this novel agent.
Experimental Design:
The antitumor effects of ZD6126 were examined using a range of solid tumor models: (a) ras-transformed mouse 3T3 fibroblasts (Hras5); and (b) human lung (Calu-6), colorectal (LoVo and HT-29), prostate (PC-3), ovarian (SKOV-3), and breast (MDA-MB-231) tumors, grown as xenografts in nude mice.
Results:
In vivo, a well-tolerated dose of ZD6126 was shown to cause rapid effects on tumor endothelium leading to exposure of the basal lamina after cell retraction and subsequent loss of endothelial cells. This led to thrombosis and vessel occlusion, resulting in extensive tumor necrosis 24 h after ZD6126 administration. Dose-response studies showed that these effects were seen at a dose 8- to 16-fold lower than the maximum tolerated dose, demonstrating that ZD6126 has a wide therapeutic margin in these mouse models. A single dose of ZD6126 (200 mg/kg) led to a significant growth delay in Calu-6 and LoVo tumors. Growth delay was increased when 100 mg/kg ZD6126 was given as a well-tolerated regime in five daily doses. Finally, combining ZD6126 with cisplatin resulted in greater than additive enhancement in growth delay in the Calu-6 model.
Conclusions:
These findings provide direct support that ZD6126 selectively disrupts tumor vasculature, demonstrate that it has activity in a range of tumor xenograft models, and show that it can significantly enhance the antitumor efficacy of cisplatin.
Insights
The novel vascular targeting agent ZD6126 effectively disrupts tumor vasculature, leading to necrosis and significant tumor growth delay in preclinical models. Combination therapy with ZD6126 and cisplatin showed enhanced antitumor efficacy.
Area of Science:
- Oncology
- Vascular Biology
- Drug Discovery
Background:
- Vascular targeting agents represent a promising strategy for cancer therapy by disrupting tumor blood supply.
- Understanding the precise mechanism of action of novel agents is crucial for optimizing their clinical application.
Purpose of the Study:
- To evaluate the antitumor effects of ZD6126, a novel vascular targeting agent.
- To elucidate the mechanism of action of ZD6126 using histological and ultrastructural analyses.
Main Methods:
- In vivo antitumor activity was assessed in various human tumor xenografts (lung, colorectal, prostate, ovarian, breast) in nude mice.
- Histology, CD31 immunohistochemistry, and electron microscopy were employed to investigate the agent's effects on tumor endothelium.
- Combination therapy with ZD6126 and cisplatin was evaluated for synergistic effects.
Main Results:
- ZD6126 induced rapid changes in tumor endothelium, leading to vessel occlusion, thrombosis, and extensive tumor necrosis within 24 hours.
- The agent demonstrated a wide therapeutic margin, with effective doses significantly lower than the maximum tolerated dose.
- A single dose of ZD6126 significantly delayed tumor growth, and combination with cisplatin resulted in enhanced antitumor efficacy.
Conclusions:
- ZD6126 selectively targets and disrupts tumor vasculature, leading to antitumor effects across a range of xenograft models.
- The findings support ZD6126's potential as a monotherapy and as an adjunct to chemotherapy, such as with cisplatin.
