Angiozyme 19/4/04. By Richard Twyman Angiozyme is a ribozyme drug in development, which can be used to inhibit the growth of new blood vessels around tumours.

The disease

Most forms of cancer involve the formation of tumours, solid masses of abnormal cells that proliferate rapidly, causing the tumour to increase in size. However, all the cells in our body require oxygen for survival, and this applies as much to the abnormal cells in a tumour as it does to our normal tissues. As oxygen can diffuse only a short distance from blood vessels, tumour growth must involve angiogenesis - the development of new blood vessels. These infiltrate the tumour and supply it with nutrients and oxygen.

Angiogenesis is an important aspect of many different types of cancer and is thought to involve an angiogenic switch, a situation in which the normal balance of proteins that promote and inhibit the growth of blood vessels is tipped in the direction of stimulation.

The target

One of the better-characterised classes of angiogenic molecules is the VEGF family, the vascular endothelial growth factors. These proteins are secreted by tumour cells and they interact with VEGF receptors, found on the surface of nearby blood vessels, causing them to sprout and send branches into the tumour. By blocking the expression or activity of the VEGF receptors, angiogenesis is inhibited and tumour growth is restricted.

The drug and how it works

Angiozyme is an unusual type of drug because it is one of a very small number of therapeutic ribozymes in clinical development.

A ribozyme is a special type of RNA molecule that has the ability to cut other RNA molecules into fragments. Typically, each ribozyme has a central catalytic domain, which does the cutting, and two arms that can attach to target RNA molecules by base pairing. In this way, a catalytic domain with no particular specificity can be made to cut up a single type of target mRNA.

The arms of the Angiozyme ribozyme specifically recognise the mRNA for FLT-1, one of the most important VEGF receptors in angiogenesis. Unlike normal drugs, which interfere with the activity of the target protein itself, ribozyme drugs destroy the mRNA and prevent the protein being synthesised in the first place.

How Angiozyme was developed

Unlike small molecule drugs, which interact with target proteins in unique and specific ways, all ribozyme drugs are based on the naturally occurring hammerhead ribozyme, and have very similar mechanisms of action. The early development of all ribozyme drugs therefore involves the same challenges, particularly those of targeting and stability.

Hammerhead ribozymes prefer to cleave the mRNA at the sequences AUC and GUC (although some variation is permitted). Therefore, it is necessary to design therapeutic ribozymes in such a way that the arms position the catalytic domain opposite an AUC or GUC sequence on the target mRNA. However, because mRNA molecules tend to fold up into complex shapes, not all of the AUC and GUC sites on the target molecules are accessible. The first stage in the development of Angiozyme was therefore to test which sites in the VEGF receptor mRNA were the most susceptible to attack, and to screen lead ribozymes to identify those with the strongest effects.

When suitable candidate ribozymes have been identified, the next challenge is to ensure they remain stable inside the body when delivered as a drug. RNA is rapidly broken down by a suite of cellular enzymes, so therapeutic RNAs are chemically modified to make them resistant to enzymatic degradation. Unfortunately, the chemical modification of ribozymes tends to interfere with their catalytic activity.

A lot of work has been carried out to determine which modifications make ribozymes stable without reducing their potency, and these optimised molecules are used in clinical trials.

Angiozyme is one of the most advanced ribozyme drugs, having undergone extensive preclinical testing and several phase I and II clinical trials. Further clinical trials are ongoing for the treatment of various types of cancer, including a combined trial with Angiozyme and chemotherapy for the treatment of metastatic colorectal cancer.

Angiozyme is likely to be the first ribozyme drug to be approved.

Image credit: K Hodivila-Dilke and M Stone