By David N. Leff

Editor¿s note: Science Scan is a roundup of recently published biotechnology-related research.

After millennia of cutting out cancers with knives, a century of burning them out with radiotherapy, and decades of poisoning them with chemotherapy, the newest buzz-mode of tumor ablation is anti-angiogenesis. That is, starving a tumor to death by interdicting its burgeoning blood supply.

Just a year ago this week, Wall Street went into a tizzy over a start-up firm called EntreMed Inc., of Rockville, Md., after the New York Times reported on May 3, 1998, that the company was developing two anti-angiogenic drugs, endostatin and angiostatin. EntreMed¿s stock rocketed 329 percent on May 4.

Boston Children¿s Hospital had licensed the two anti-tumor drugs to EntreMed. (See BioWorld Today, April 7, 1998, p. 3, and BioWorld Financial Watch, May 11, 1998, p. 1.)

Their discoverer, surgeon Judah Folkman, at the hospital, had presented endostatin and angiostatin to the world late in November 1997. (See BioWorld Today, Dec. 2, 1997, p. 1.)

The acknowledged father of anti-angiogenesis, Folkman has for more than three decades been developing tactics and strategies for shutting off the body¿s donation of lifeblood to tumors bent on ending that life.

Folkman has co-authored a seminal article in the current issue of Science, dated April 30, 1999, titled: ¿Effects of angiogenesis inhibitors on multistage carcinogenesis in mice.¿ It makes the sobering but optimistic point that it will take at least three separate anti-angiogenesis silver bullets, acting in sequence, to stop a tumor on the run.

The paper described treating mice as their solid tumors evolved through three distinct stages of progressive growth, each requiring a different blood vessel-abolishing strategy:

Prevention, aimed to strangle a nascent tumor in its hyperplastic cradle by blocking the angiogenic switch before the first malignant cells began to sprout blood vessels.

Intervention, to check the expansive growth of those cells into a stage requiring an ever-larger blood supply.

Regression, in mice with substantial tumor burden, and near death, trying to achieve progressive shrinkage of their tumors.

To treat each of these three stages, the researchers mustered an arsenal of four angiogenesis inhibitors, endostatin, angiostatin, BB-94, under development by British Biotech Pharmaceuticals plc, of Oxford, U.K., and AGM1470, from the Takeda-Abbott Pharmaceuticals joint venture, TAP.

Transgenic mice programmed to come down with pancreatic islet carcinoma served as in vivo tumor models. Each pancreas normally carries 400 insulin-secreting islets of Langerhans. As the animals mature through their average 13.5-week lifetime, their islets turn malignant, and switch on angiogenesis as they grow into solid tumors.

In the prevention stage of treatment, endostatin and angiostatin reduced angiogenic switching by some 60 percent, and BB-94 reduced it by 50 percent. AGM-1470 was virtually without effect. In the intervention trial, AGM-1470 reduced tumor growth by 82 percent, BB-94, endostatin and angiostatin by 83, 88 and 60 percent, respectively.

In the regression tests, the team assessed lifetime extension as well as tumor burden reduction. At that final stage, the mice were within two weeks of death from their cancers. All four of the angiogenesis inhibitors added at least two weeks to their survival, but they differed significantly in tumor-diminishing efficacy.

The authors concluded that their study ¿strengthens the proposition that angiogenesis inhibitors will become important components of anticancer treatment strategies, by using compounds and dosing regimens fine-tuned to target specific stages of disease progression.¿

Vitamin A Precursor Helps Prevent Cancer, But Hikes Risk In Smokers And Asbestos Workers

Generations of conscientious parents have been pushing spinach on their young children as a source of iron. Like other green, leafy vegetables, spinach is also a source of beta-carotene, which is a precursor of vitamin A. Beta-carotene gets its name from carrots, another rich source of the pigment. So are most yellow fruits.

But the richest source of all is the health food store, which sells concentrated beta-carotene supplements as an antioxidant.

Epidemiological surveys support the hypothesis that beta-carotene can prevent cancer in humans. But a brief article in the current issue of Nature, dated April 29, 1999, reports a caveat. The paper¿s title tells that cautionary story: ¿Co-carcinogenic effect of beta-carotene.¿

The article reports several chemoprevention studies which suggested that heavy smokers and workers exposed to asbestos should avoid high-dose carotene supplements because of an increased risk of lung cancer. Its senior author, environmental toxicologist Marvin Legator, at the University of Texas Medical Branch, in Galveston, found ¿a highly significant increase in carcinogen-metabolizing enzymes¿ in the lungs of rats he fed high doses of beta-carotene.

¿In humans,¿ his paper pointed out, ¿correspondingly high levels of [such carcinogens] would predispose an individual to cancer risk from the widely bioactivated tobacco-smoke procarcinogens.¿

¿What we¿re saying,¿ Legator told BioWorld Today, ¿just on the basis of our animal studies, is explaining that some of those studies were paradoxical. They showed that beta-carotene really reduces the rate of cancer, but on the other hand, with high-risk groups that are already exposed to carcinogens, it increases the risk.

¿So, what our in vivo mechanistic study does,¿ Legator went on, ¿is offer one explanation of why you get different results with different populations. This is significant in terms of public health. One of the conclusions that could be drawn from these rat results is that people who are already at risk for cancer possibly should go easy on beta-carotene supplements. Quitting smoking, of course, would be perfect.¿ n