A happy ending to the tadpole's tail: An enzyme first found in frogs may lead to new drugs for cancer, arthritis and some eye diseases. Tim Cawston reports

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The Independent Online
IN A FEW weeks' time our ponds will be brim full of tadpoles. Come summer, they will lose their tails in a process that has long puzzled scientists. What makes their tails disappear? They do not wear away. They do not dissolve.

Thirty years ago one scientist who asked this question discovered an enzyme in the tails with a critical role. This now looks likely to lead to new drugs for arthritis, some cancers and eye diseases.

Tadpole tails represent about an eighth of the tadpole's body weight. They are made up of the body's most abundant protein, collagen, a rod-shaped molecule highly resistant to enzymes that scientists know will break down proteins.

In 1962, Jerome Gross in Boston found that the resorbing tails contained an enzyme that chops collagen three-quarters of the way from one end. Gross called it collagenase. He found that any connective tissue, from cartilage to cornea, can produce collagenase. In fact, all connective tissues in vertebrates produce an enzyme that can break them down.

Connective tissues consist of strong rope-like fibres of collagen with another protein, proteoglycan, in between them. This acts like a giant sponge and pulls water into the tissue. This means that tissues such as cartilage, which contain a lot of proteoglycan, can act as shock absorbers.

But it is the cells within connective tissue that are most important. These cells make the collagen and proteoglycan, but they also make the enzymes that can break them down. So a crucial balance exists between the amount of tissue and the amount of enzymes. Too much enzyme and the connective tissue begins to disappear.

In the Seventies, scientists discovered a whole family of enzymes like collagenase called matrix metalloproteinases (MMPs). These potent enzymes are like biological scissors that can chop up all parts of connective tissues but are only made by cells as and when they are needed.

In healthy tissues MMPs are used to get rid of unwanted tissue such as a tadpole's tail, a mother's uterus after the birth of her baby or as wounds heal. Only very tiny amounts of enzyme are needed. Just one milligram of collagenase can destroy three million milligrams (three kilograms) of collagen in just one hour.

These enzymes are so potent that they have to be carefully controlled. Sometimes they get out of control and over a period of time just a small imbalance between the amounts of collagen and proteoglycan made and the amounts broken down can lead, for example, to the destruction of cartilage that is found in rheumatoid arthritis. But how should these potent enzymes be controlled?

Each MMP is made with an extra section attached that must be chopped off before the enzyme can do its job. During the Eighties scientists found that MMPs could be divided into three main types - collagenases, stromelysins and gelatinases. Although these are quite similar, each type chops up

a different protein in connective tissue.

But there is another very important way to control MMPs. Cells make a specific inhibitor of MMPs called Timp (tissue inhibitor of metalloproteinases). Timp binds very tightly to the active forms of the MMPs. This prevents the enzymes from separating off and doing their job.

These three main chopping enzymes are responsible for the destruction of connective tissues in a wide variety of diseases. They play a part in the slow but relentless destruction of cartilage in rheumatoid arthritis, where the shock- absorbing properties are lost and patients' joints are damaged and painful. In some cancers they are used to release tumour cells so they can move around the body to form more tumours.

These tumour cells move from primary tumours through connective tissue, secreting MMPs. The enzymes punch holes in blood vessels and let cells move through the blood to other parts of the body.

Cancer patients could benefit from drugs that inhibit MMPs, and not only in stopping the development of secondary tumours. Tumours develop their own blood supply. MMP inhibitors could prevent this, and so slow the rate of growth of the tumour itself. If a tumour was detected at an early stage, treatment could prevent tumours developing in other parts of the body before the doctors removed or killed the tumour by surgery or radiotherapy.

Scientists believe MMPs are also involved in the breakdown of the cornea in people with eye diseases. In the cornea, if ulcers form, the transparent tissue is rapidly broken down, forming a scar that prevents normal sight. MMP inhibitors could prevent this initial rapid destruction.

These inhibitors could form the basis of drugs for patients where cartilage and bone slowly disappears - in diseases such as rheumatoid and osteo-arthritis.

But can the MMPs be stopped from working? Several large pharmaceutical companies are developing drugs to block the enzymes by trying to mimic the action of the Timp. They have managed to prevent some cancer cells from moving through connective tissue.

In experiments, invasive tumour cells easily moved through connective tissue. However, when scientists added Timp or the new synthetic inhibitors, the invasive tumour cells could not move.

Laboratory tests also showed that the synthetic inhibitors prevented cartilage from breaking down.

There is much more work to do before these drugs will be ready. Scientists do not know how long they will survive in the body, or what dose to use. What is needed now is stronger inhibitors that will inhibit just one type of MMP, but not the others.

This is closest to what happens naturally in the body's cells, and therefore could mean drugs with fewer side effects.

Scientists at the Rheumatology Research Unit of Addenbrooke's Hospital in Cambridge and a group at Imperial College, London, are making crystals of the MMPs to uncover their 3D shape. This should allow them to make very specific inhibitors that will selectively target each MMP individually.

(Photograph and graphic omitted)

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