By David N. Leff

Until the media ran Viagra up their flagpoles, this year's buzzword of medical research and development was angiogenesis.

What set off that furor was an article in Nature, dated Nov. 27, 1997, disclosing discovery of two compounds, each of which strangled a tumor's blood supply. That report was titled "Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance." (See BioWorld Today, Dec. 2, 1997, p. 1.)

Those two angiogenesis inhibitors, dubbed angiostatin and endostatin, were discovered by clinical oncologist Michael O'Reilly, a research associate in the laboratory of surgeon Judah Folkman, at Harvard University affiliated Children's Hospital, in Boston.

Some 40 laboratories, industrial and academic, are now reportedly hard at work to carry forward production and testing of these two putative anticancer agents, and hasten their trials in human patients.

One of these researchers is Ralph Weichselbaum, chairman of the radiation and cellular oncology department at the University of Chicago. He is senior author of a paper in today's Nature, dated July 16, 1998. Its title is "Combined effects of angiostatin and ionizing radiation in antitumor therapy."

Ionizing radiation is the second weapon in clinical oncology's war against cancer. After surgery has carved away the bulk of a solid tumor, and before chemotherapy attempts systemically to check its regrowth and metastasis, radiation treatment aims locally at cleaning up malignant cells on the margins left by the surgeon.

Alternatively, wielding electrically charged, ionized atoms rather than scalpels, radiation may itself ablate a cancerous growth.

"Radiation works well with other therapeutic modalities," Weichselbaum told BioWorld Today, "or where you really escalate the dose."

O'Reilly, who discovered the angiogenesis inhibitors, like Weichselbaum trained as a radiation oncologist. Regarding radiotherapy's Catch-22 dilemma, O'Reilly observed, "Ionizing radiation is a very good clinical modality, but the problem is in order to get adequate control of the tumor you have to push the dosage to such levels that you damage the surrounding tissues and that sometimes causes significant side effects.

Or, the other side," O'Reilly pointed out, "is that because you're worried about the surrounding tissues, you can't go up to the doses that you think would be effective."

Paper Seen As 'Landmark' In Clinical Oncology

"Weichselbaum and his paper show that in fact, now with angiogenesis inhibitors, you should be able to start using them with modalities such as radiation therapy much more effectively," O'Reilly said.

"I think his paper in Nature," he commented, "is definitely going to be the landmark study. It's going to be one of those papers that really — maybe in a very short time — changes peoples' thoughts dramatically, particularly clinicians.' The applications aren't just for radiation therapy. It also demonstrates — what we've been speculating all along — that angiogenesis inhibitors are going to be a great platform to make other therapies work better."

Weichselbaum arrived at his demonstration by serendipity.

"I was working on radiation-inducible gene therapy," Weichselbaum recalled, "and we found it to be anti-vascular. The treatment was causing thrombosis, but when we anti-coagulated the mice, we still got an effect. We then found that these animals were by serendipity producing angiostatin from the combination of our gene therapy with radiotherapy. But we have been as yet unable to prove it, so we haven't published.

"But it gave us a lead. We thought: 'What if we add exogenous angiostatin with radiation?' — and that's really how we got started doing it. Completely serendipitous."

What Weichselbaum and his co-authors got started doing was a series of experiments testing what effects angiostatin, with and without radiation, might have in nude mice.

"The rationale for our tests wasn't exactly published in Nature," he said," but it was based on our serendipitous experiment."

Angiostatin/Radiation Combo Suppresses Tumors

"So the first thing we did," Weichselbaum recounted, "was dose response with angiostatin alone. Then three tumor regression experiments, with angiostatin, angiostatin plus radiation, and radiation alone. We found the superior regression rate in three human xenograft tumors — malignant glioma, squamous cell carcinoma and prostate adenocarcinoma — as well as a mouse Lewis lung carcinoma tumor."

Low-dose angiostatin together with low-dose radiation therapy proved far more effective at suppressing established tumors than either full-dose treatment alone.

"We then asked," Weichselbaum went on, "'Gee, could this effect be in the tumors' blood vessels?' So we cut up the tumors and found less vessel density in those of the animals that got combined therapy than with any other treatment.

"Then we asked, 'Is this specific for endothelial cells [the inner lining of blood vessels]?' So we looked at some tumor cells in angiostatin. When we saw no sensitizing — enhancing — effects on them, we concluded that angiostatin plus radiation had an effect primarily in the tumor vasculature, the target of angiogenesis inhibition."

Asked about the prospect of trying his radiation/angiostatin combo in human patients, Weichselbaum said, "I think it's definitely something I'd be willing to try, because it's not toxic in animals. If I could get enough angiostatin and endostatin," he concluded, "I'd do it in humans tomorrow."

Not tomorrow, but within a year, O'Reilly indicated. "The National Cancer Institute is in the process of transferring our angiogenesis inhibitor technology," he told BioWorld Today, "so they can scale up production in their facilities and begin a limited study in 30 cancer patients — 15 here in Boston; 15 at NCI, in Bethesda, Md.

"I don't know if it will be a Phase I trial per se," he added, "or more like a proof-of-principle study — the way they did with Taxol — to convince the pharmaceutical industry, which actually has been very committed, to focus on this primarily." *

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