Apr. 7, 2000 GAINESVILLE, Fla. --- A drug that indirectly attacks tumors by destroying the blood vessels that feed them substantially boosts the effectiveness of traditional anti-cancer medications in laboratory animals, new University of Florida research shows.
Scientists found that by combining combretastatin A-4 prodrug with standard chemotherapy agents, tumor cells in mice were killed off at 10 to 500 times the rate of chemotherapy alone.
The drug was employed against human tumor cells - breast, ovarian and AIDS-related Kaposi's sarcoma - that had been injected into the animals.
"We previously had shown that the drug was effective when combined with radiation therapy," said Dietmar Siemann, a professor of radiation oncology in UF's College of Medicine. "But now we have shown that it performs well with traditional anti-cancer drugs. It does well on its own, but it's also a way to enhance the effectiveness of chemotherapy."
Siemann and his colleagues presented their findings earlier this week at the American Association for Cancer Research meeting in San Francisco. He was joined by UF graduate student Lingyun Li and pathologist Amyn Rojiani of the University of South Florida.
Combretastatin, a small organic molecule first identified in the bark of the African bush willow, is part of a new class of compounds that target a tumor's vascular system. The drug differs from the "anti-angiogenesis" medications that have received a lot of attention in that it attacks existing and growing tumor vessels rather than preventing the formation of new ones.
Earlier research by Siemann was supported in part by OXiGENE Inc., the developer of combretastatin. The Boston- and Sweden-based biopharmaceutical company finalized an agreement in December to transfer the cancer therapy development rights for the drug to Bristol-Myers Squibb Co.
Combretastatin currently is being tested in Phase 1 trials of patients with advanced cancers. Siemann anticipates that the drug will move onto larger Phase 2 studies within the next few months. In general, small Phase 1 and Phase 2 trials are designed to determine preliminary safety and effectiveness issues. If results are positive, the drug is then tested in a larger, final clinical study that sometimes involves thousands of patients.
Siemann said he wanted to explore the use of combretastatin in Kaposi's sarcoma, the most common kind of tumor in AIDS patients, because there aren't many good treatments available.
"Kaposi's sarcoma is also a highly vascularized tumor, so it makes sense to try agents that target the vessel system at the disease site," said Siemann, who recently received a $1.4 million grant from the National Institutes of Health to continue his research on vascular-targeting agents.
Because the immune system of people with AIDS is sometimes greatly compromised, they often can receive just a limited amount of standard chemotherapy.
"We found that even by itself, combretastatin is very effective in this model of Kasposi's sarcoma," Siemann said, noting that after an injection, viable tumor cells existed only at the periphery.
When it was combined with drugs typically prescribed for Kaposi's sarcoma -- cisplatin or vinblastine -- tumor cell survival in Kaposi's sarcoma was just one-tenth of that seen with any of the drugs alone. Researchers measured tumor cell survival a day after the medications were injected.
In breast and ovarian tumors models, combretastatin with cisplatin or cyclophosphamide caused a dramatic increase in tumor cell death - a 10- to 500-fold increase-- over any of the medications by themselves.
Combretastatin by itself does not eradicate an entire tumor because it attacks only new blood vessels that have developed to support the cluster of cancerous cells. The outer rim survives because it is nourished by blood vessels that supply normal tissue.
"That's why we use it in combination with other chemotherapy," Siemann said. "That's also very positive, because normal tissue is preserved."
"Combretastatin has great promise," said Amato Giaccia, an associate professor of radiation oncology at the Stanford University School of Medicine. "It ranks at least as well as the other anti-angiogenic compounds in clinical trials."
Giaccia noted that several laboratories around the world are finding similar results with combretastatin and a variety of tumor types. That's encouraging, he said, because "it's getting real and reproducible effects."
"One always needs to interpret animal models cautiously," he continued. "But on the other hand, if you can't cure a tumor in an animal first, your chances of curing a human tumor later are greatly diminished."
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