How do ZYBRESTAT (fosbretabulin) and OXI4503 work?

(Note: fosbretabulin was previously referred to as "combretastatin" and "CA4P")

ZYBRESTAT (fosbretabulin) kills tumors by attacking the blood vessels that supply them with oxygen and nutrients.

After a short intravenous infusion, ZYBRESTAT™ rapidly spreads throughout the patient's bloodstream. As it spreads ZYBRESTAT™ is converted to its active form, fosbretabulin, which enters the endothelial cells that line the blood vessels.

In tumors, these cells are immature and thus particularly sensitive to fosbretabulin's effects as compared to the endothelial cells in normal tissue.

Once inside the endothelial cells that line the tumor vasculature, fosbretabulin destroys the internal skeleton of the cells and changes their shape from flat to round, effectively plugging the capillaries that feed the tumors.

This theory was initially demonstrated in Phase I clinical trials through blood-flow imaging of cancer patients with solid tumors. Statistically significant reductions in tumor blood flow were demonstrated by blood-flow imaging measurements four to six hours following the infusion of ZYBRESTAT.

What is the difference between the action of ZYBRESTAT (fosbretabulin) and anti-angiogenesis drugs?

Fosbretabulin causes the vascular structure inside a solid tumor to collapse, depriving the tumor of blood and oxygen that it needs to survive.

Anti-angiogenesis drugs attempt to keep new blood vessels from forming. They do not act on blood vessels that already feed existing tumors.

Can I see the effects of ZYBRESTAT in animal studies?

Voice Script from Video:

This movie was supplied by the Tumour Microcirculation and Advanced Technology Development Groups at the Gray Cancer Institute, Mount Vernon Hospital, Northwood, UK. (http://www.gci.ac.uk) With special thanks to Gill Tozer, Boris Vojnovic and Ian Wilson.

Combretastatin A4-P as a tumor vascular targeting agent.

This is a tumor viewed under the microscope. A large blood vessel can be seen running across the surface of the tumor. This vessel is draining the waste products from the tumor tissue.

At high magnification, you can see the individual red blood cells flowing through the vessels. Generally, the blood flow is moving very fast, efficiently supplying the tumor with the oxygen and nutrients it needs for growth. However, some of the tumor tissue lies quite far away from the blood vessel, and if you look carefully you'll see that some vessels are flowing quite slowly and the red cells are spaced far apart. This suggests that even before giving a drug, there are some tumor regions that are nutrient deprived and hypoxic. These regions are a problem for many conventional cancer treatments. But in the future, it may be possible to specifically target them. In a moment, you'll see the effects of Fosbretabulin on these flowing vessels. The drug disrupts one of the proteins, which makes up the skeleton of living cells. The dividing cells, which line the inside of tumor blood vessels, appear to be particularly sensitive to this drug. One of our main aims is to find out why this should be so.

Here's the effects of combretastatin now. This is the same tumor region 10 minutes after giving combretastatin. As you can see, the effects are dramatic. The rates of blood flowing through the vessels has decreased enormously and the vessels are a lot narrower. And now it's one hour, fifty minutes after drug administration. Many of the vessels have disappeared from view completely. This may be because other vessels upstream have become blocked so that blood is no longer flowing. Some of the vessels clearly contain stagnant blood. It's effects such as these that make combretastatin a promising vascular targeting agent.

And now we're having a look at different regions within the tumor after treatment with combretastatin. This is the edge of the tumor, where blood is still flowing, albeit very slowly.

Here's the vessel we saw at the beginning, and there's very little flow here… or here.

Here's the low power view again after treatment.

Can I see the effects of ZYBRESTAT in animal studies?

What is the difference between the action of ZYBRESTAT and anti-angiogenesis drugs?

How does ZYBRESTAT (fosbretabulin) work?