By David N. Leff

Children in the U.S. are often given tea, while their parents drink coffee, on the mistaken notion that tea has little or no caffeine. In fact, a typical cupful contains anywhere from 60 mg to 90 mg of caffeine, depending on the type of tea -- black, green or oolong -- and how long it's brewed. A cup of coffee packs 70 mg to 200 mg.

Tea is known as the source of several B-complex vitamins. And today's issue of Nature, dated June 5, 1997, carries a one-page scientific report titled "Why drinking green tea could prevent cancer."

Its lead author is tumor biologist Jerzy Jankun, at the Medical College of Ohio, in Toledo.

"I'm not a specialist in green tea," Jankun told BioWorld Today. "We are working on urokinase, our major interest. It was an accident that we discovered a green tea connection."

That bit of serendipity came out of a computer search for compounds that might inhibit urokinase, an enzyme implicated in carcinogenesis. "One of those compounds," he recalled, "was a major ingredient of green tea. We didn't know for quite a few weeks that we had a green tea connection."

Proteolytic Enzyme Triggers Quest For Inhibitor

Urokinase, Jankun observed, "is very seldom produced in the body -- mostly during wound healing, pregnancy or bacterial invasion. But during the process of carcinogenesis, especially metastasis, urokinase is one of the most frequently overexpressed enzymes in human cancers.

How does urokinase do this dirty work?

"As a proteolytic enzyme," Jankun explained, "urokinase activates a different proteolytic enzyme, plasminogen, which in turn activates plasmin, which attacks various proteins. Basically it's making room for tumor expansion, by digging some kind of a tunnel that the cancer cells can migrate through."

Some of that tunneling permits new blood vessels to make their way to growing tumors. "On the tip of such a capillary," Jankun said, "you have high expression of urokinase, promoting that angiogenesis."

With regard to its urokinase activity, tea comes in three quite distinct persuasions:

Green tea, which comprises 20 percent of the beverage consumed in the world, is fancied mainly in Asian countries. It contains a compound that, Jankun discovered, inhibits urokinase production.

Black tea, the 78 percent consumed mainly in Western countries, involves a manufacturing process -- so called "fermentation" -- that knocks out the urokinase inhibitors that Jankun and his co-authors have found in green tea. At 2 percent, semi-fermented oolong tea is a minor player among the 2.5 million metric tons of tea manufactured annually.

In analyzing the key components of green tea, Jankun's group "found out a different and novel mechanism of its anticancer activity," specifically, a polyphenol, or cathechin, called epigallo-cathechin-3 gallate (EGCG for short).

This component, he reported in Nature, binds to urokinase, blocks certain of its catalytic amino acids, and thus inhibits its enzymic activity by interfering with its ability to recognize its substrate.

Laboratory experiments in vitro showed the Ohio group that it not only curbed metastasis, Jankun added, "but also shrank a tumor.

"EGCG can be used eventually in anticancer therapy," he pointed out. "It explains the ability of green tea to prevent or slow down the growth of various tumors."

Amiloride, a widely prescribed diuretic for controlling high blood pressure and congestive heart failure, is known to inhibit urokinase. "It would have the same effect as green tea," Jankun observed. "However, the problem is that if you would like to use amiloride, you have to increase the dose, and I don't know how far it will be tolerated by the body."

Commercial Partner Joins Drug Discovery Effort

Obviously, he and his industrial collaborator, American Diagnostica Inc., of Greenwich, Conn., are now in hot pursuit of a more effective therapeutic urokinase blocker, based on the EGCG that the computer turned up. "American Diagnostica has supported us for many years in this area, and is collaborating in this particular work," Jankun concluded.

The privately held company's chairman and president, Richard Hart, told BioWorld Today: "Jankun's work is part of our long-range programs to discover antineoplastics. We're particularly interested in the interaction of urokinase, which we define as a ligand, with its receptor, a cell-surface binding site. That to us is an important causally related factor in tumor cell invasion, penetration and metastasis." Jankun and Hart are co-inventors of the patent application now pending.

The latter's research group is "specifically working on the tumor proteolytic agent, the receptor-ligand binding cascade, and its role in the survival, extension and relocation of cells," Hart said.

He concluded: "Our company has synthesized and put into animal models the molecules Jankun's computer modeling revealed, particularly to screen for prostatic cancer."

At McGill University's department of medicine, oncology and physiology, in Montreal, clinician and researcher Shafaat Rabbani runs a laboratory focused on the role of urokinase in tumor progression.

"What Dr. Jankun has done," Rabbani said, "is describe a small molecule which is a main ingredient of green tea and has anti-urokinase activity. If that is true, it is a very novel observation, and probably explains why it got rapid publication in Nature. *