New Angiogenesis Inhibitors May Bypass Drug Resistance

NEW ORLEANS—A new generation of angiogenesis inhibitors has been shown to shrink large tumors in mice, without toxicity and without the development of drug resistance, Judah P. Folkman, MD, said in the Honor Lecture in Physiology at the American College of Chest Physicians annual meeting.

Dr. Folkman, professor of cell biology and Andrus Professor of Pediatric Surgery, Harvard Medical School, called the latest developments in angiogenesis research some of the most encouraging findings yet, not only in the area of angiogenesis but in all of cancer management. “The concept that angiogenic therapy can bypass drug resistance is most exciting. It has changed our thinking and may, in fact, change the way we manage cancer,” he said.

First-generation angiogenesis inhibitors, now in clinical trials, have the ability to suppress angiogenesis and check tumor growth. Now, a second generation of more powerful agents that inhibit vascular endothelial cells may be able to stop angiogenesis completely and cause tumor regression.

Researchers in Dr. Folkman’s lab have identified two naturally occurring substances with this potential—angiostatin, an internal fragment of plasminogen, which is involved in blood clotting, and endostatin, an internal fragment of collagen 18, a protein found only in the blood vessel wall.

Angiostatin is highly specific as an inhibitor of endothelial growth but has no effect on other tumor cells, normal epithelial cells, or fibroblasts. It is the first specific endothelial inhibitor, he said.

Injections of angiostatin into mice with very large tumors (1% of body weight, or the equivalent of a 1.5-pound tumor in humans) produce tumor regression, he said, while discontinuation of the injections results in tumor regrowth. The death of tumor cells with this agent is by apoptosis, not necrosis, and his laboratory has not found a tumor type that cannot be made to regress in this manner with use of angiostatin.

“Treated tumors regress and become invisible in the mouse after 15 days of therapy. And if you give antiangiogenic therapy before chemotherapy, it sensi-tizes the tumor so that only a few doses of chemotherapy will eradicate the tumor,” Dr. Folkman said. “Treated mice have all the signs of healthy mice.”

Lack of Drug Resistance

Experiments with endostatin in four mice with large tumors have been even more compelling. In this study, led by Dr. Michael O’Reilly (JAMA, November 27, 1997), untreated animals died at 3 weeks, but tumors disappeared in mice receiving daily SC endostatin injections.

When the tumors disappeared, the therapy was stopped. The tumors then reappeared and were allowed to grow to 2% of body weight. Again the animals were injected, and again the tumors disappeared, as did lung metastases, suggesting that the vascular endothelial cells on which endostatin acts do not develop resistance to the agent.

The most exciting aspect of the experiment, however, was an unanticipated finding that occurred far down the line and was consistent in all animals. After two or more re-treatment cycles, the tumors not only disappeared but did not return. Just as surprisingly, each mouse followed the same time course, with all tumors disappearing within 7 days of each other, as if on schedule.

“The effect is durable. All the mice are healthy, and no tumor has come back,” Dr. Folkman said. “Perhaps the tumor is dormant and we can’t see it. But why did all four tumors ‘know’ within 3 to 7 days of each other to stop growing?”

Further experiments found similar “time clocks” in other tumors: a 160-day clock in fibrosarcomas and an 80-day clock in melanoma. “Every tumor has its clock,” Dr. Folkman commented.