Researchers Report Significant Delays In Tumor Growth In Mice Treated With Two New Drugs

November 19, 2003

GAINESVILLE, Fla. — University of Florida medical scientists reported today they have significantly delayed the growth of cancerous human tumors in mice by combining a new drug that thwarts blood vessel formation with another new drug that destroys existing vessels.

Addressing an international cancer research conference in Boston, UF radiation oncologist Dietmar Siemann, said combined use of two experimental drugs – which rob tumors of their blood supply – was more effective in delaying tumor growth than either of the drugs used alone. The annual meeting is held jointly by the National Cancer Institute, the American Association for Cancer Research and the European Organization for Research and Treatment of Cancer.

Siemann, a professor of radiation oncology with the UF College of Medicine and the UF Shands Cancer Center, said animals with kidney tumors or Kaposi’s sarcoma, an aggressive cancer associated with AIDS, responded well to the drugs, with no apparent adverse effects. The therapy involved daily injections of the anti-angiogenesis drug for one week, and once-a-day injections of the vascular targeting agent on the Monday, Wednesday and Friday of that same week. The study involved 35 mice.

The two drugs – an anti-angiogenic drug, called ZD6474, that blocks the growth of new blood vessels and a vascular targeting agent, ZD6126, that damages and destroys vessels already in place – are now being tested in cancer patients through phase 2 clinical trials, but the combination therapy has thus far been limited to research in laboratory animals.

Siemann said the results of his latest studies in mice harboring human malignant tumors indicate that targeting the vasculature inside tumors may prove to be a valuable addition to the treatment of human cancers. The strongest rationale, he said, is the fact that solid tumors are dependent on blood vessels to supply oxygen and other nutrients and to remove waste products.

“When we used only the anti-angiogenic drug in treating mice with kidney tumors and Kaposi’s sarcoma, we achieved tumor growth delays of 25 and 15 days, and with the sole use of the vascular targeting drug we achieved tumor growth delays of 23 and 25 days,” Siemann said. “But when we combined the two drugs in the treatment of mice with the same types of malignancies, we documented tumor growth delays of 55 and 86 days.”

Treatment was not begun until the human tumors growing inside each mouse reached the approximate size of a pea, large enough to be detected by physical examination.

“Our findings seem more exciting in light of the fact we achieved these antitumor effects with the use of very nontoxic doses of the two selected drugs, and we were dealing with two forms of human cancer that are stubbornly difficult to treat,” said Siemann, whose findings on vascular targeting therapies have been reported in The International Journal of Cancer and in Seminars in Radiation Oncology.

“In our latest study, we found that while some tumor types responded better than others, the antitumor response was always enhanced when the two treatments were combined,” he added. “In one study, we were delighted to find that three of eight treated mice were free of any indications of cancer a year after treatment, indicating they are cured.”

Siemann added that more extensive research is needed to determine whether the beneficial effects observed in mice can be duplicated in human cancer patients.

“Targeting the vascular supply of tumors has for a long time been considered a potential new weapon in cancer therapy, but efforts to inhibit new blood vessel development or to damage the already established vessels in tumors has not achieved the expected level of success,” said Michael Horsman, an associate professor of experimental clinical oncology at the Aarhus University Hospital in Aarhus, Denmark. “Dr. Siemann’s preclinical studies using human tumors have now demonstrated that substantial benefit can be achieved by combining these therapies.”

The concept of using anti-angiogenic drugs to interfere with and halt new blood vessel growth was pioneered in animal research by Dr. Judah Folkman, a cancer researcher at Harvard University. The late Juliana Denekamp, of Umea University, Sweden, is credited with developing the concept of using vascular targeting agents that directly damage blood vessels and thereby kill tumor cells by starving them of nutrients. Their findings in animals, which gained national attention in 1998, have inspired thousands of follow-up studies.

Siemann said recent findings at UF and elsewhere now suggest strong potential benefits to be derived from further testing of combined anti-angiogenic and vascular targeting drugs, and that, in his view, this drug duo also should be evaluated in combination with conventional chemotherapy and/or radiation therapy for various types of cancer.

He conducted his latest studies with co-investigator Dr. Wenyin Shi, an assistant professor of radiation oncology at UF. Their ongoing research is supported by the National Cancer Institute and AstraZeneca Pharmaceuticals, an international company that produces both the anti-angiogenic and vascular targeting agents.