By Victoria White
GAINESVILLE, Fla.---A substance first identified in the bark of an African tree magnifies the tumor-cell killing power of radiation therapy by as much as 500 times in laboratory animals, University of Florida researchers reported today (11/23/98).
"We are always pursuing new avenues to enhance our conventional cancer therapies, radiation and chemotherapy," said Dietmar Siemann, a professor of radiation oncology in UF's College of Medicine. Siemann, his graduate student Lingyun Li and pathologist Dr. Amyn Rojiani, of the Moffitt Cancer Center in Tampa, authored the paper in the November issue of the International Journal of Radiation Oncology, Biology, Physics.
"The results with combretastatin A-4 prodrug are very encouraging. We're able to achieve these effects by giving relatively low doses that produce no side effects in mice," Siemann said.
Combretastatin A-4 prodrug, one of a new class of compounds that launch an indirect attack on tumors by interfering with their blood supply, is seen as a potentially effective therapy for solid tumors, which represent the vast majority of cancers.
Siemann's research was supported in part by a grant from OXiGENE Inc., the developer of the drug. Earlier this month, the Boston- and Sweden-based biopharmaceutical company announced it has begun Phase I clinical trials in human patients with advanced cancers to test the safety and maximum tolerated doses of combretastatin.
Following successful Phase I trials, further clinical testing would be required to measure the drug's effectiveness, to determine dosages and to compare its tumor-destruction results with standard treatments.
Combretastatin, a small organic molecule found in the bark of the African bush willow tree Combretum caffrum, was identified a decade ago by George R. Pettit, and his colleagues at Arizona State University. In collaboration with the National Cancer Institute and the Gray Laboratory in the United Kingdom, they have since demonstrated it can kill tumor cells in animal models and be manufactured synthetically. UF's research sheds additional light on their original findings.
Like other new compounds that indirectly fight tumors, combretastatin A-4 prodrug targets the blood vessels that sprout up to nourish cancerous growths. The idea of battling tumors by attacking their life support system has long been championed by Judah Folkman, a physician and cancer researcher at Children's Hospital in Boston who has received worldwide attention for his work.
"The combretastatin approach is a little different from what Dr. Folkman has been doing," said Siemann. "The majority of research has focused on preventing the growth of new tumor blood vessels, the anti-angiogenesis strategy. What we are doing is attacking existing and newly formed tumor blood vessels directly by exploring a key difference between these vessels and those found in normal tissues.
"Tumor vessels contain significant numbers of dividing blood vessel cells, and we and others have shown that these dividing cells can be selectively damaged by combretastatin. This approach leads to rapid and catastrophic shutdown in the vessels that serve the tumor, resulting in extensive tumor cell death."
Just 24 hours after Siemann administered the compound to mice, the damage to the cancer's blood vessels was so extensive that viable tumor cells were seen only at the outside edges of the tumors. Siemann believes that these tumor cells survived because at its periphery, a tumor is sustained by the body's normal blood vessels rather than those that have developed specifically to support the cancerous growth. Normal, non-dividing blood cells are not susceptible to combretastatin.
"The strategy is to kill those surviving tumor cells with conventional treatment, such as radiation therapy or chemotherapy," he said.
Combretastatin also was able to kill off oxygen-starved tumor cells, which resist radiation and some forms of chemotherapy, Siemann said.
Another study published in the same journal as Siemann's research found that combretastatin was effective in battling transplanted and spontaneous tumors in animal models. Michael Horsman, a researcher on the second study who is affiliated with the Danish Cancer Society's department of experimental oncology, called the combretastatin results "very compelling, particularly in the case of the spontaneous tumors, which represent a more clinically relevant model."
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