PHILADELPHIA — The ABCs of fighting cancer these days include two big words that describe exciting basic concepts. One is anti-angiogenesis, a strategy to stop or prevent the growth of blood vessels needed to nourish a tumor and allow it to spread. Another approach is chemoprevention—using medication to halt, delay or reverse the development of cancer.
According to new prevention research by Fox Chase Cancer Center cell biologist Margie Clapper, Ph.D., of Harleysville, Pa., and colleagues at Cephalon Inc. in West Chester, Pa., the drug Oltipraz holds the potential to achieve both goals. A report on the ongoing studies appears in the January 2002 issue of Clinical Cancer Research. Co-authors include Dr. Clapper and Bruce Ruggeri, Ph.D., of Cephalon’s Division of Oncology.
Clapper has been studying Oltipraz for more than a decade, concentrating on its ability to raise blood levels of protective “detoxification” enzymes that help ward off cancer. These enzymes resemble antioxidant compounds in broccoli, cabbage and similar vegetables.
In early clinical studies, Clapper worked with Fox Chase medical oncologist Christine Szarka, M.D., to see how well Oltipraz increased protective enzymes among people at high risk of colon cancer. For comparison, some trial participants took dried broccoli tablets instead of the drug. Oltipraz surpassed the dietary approach by a significant measure with few or no side effects. A later study used Oltipraz for people at risk of lung cancer.
Most recently, with support from the Cancer Research Foundation of America, Clapper has focused on individuals with ulcerative colitis, which increases the risk of colon or rectal cancer by 10 times. In studies with laboratory mice, Oltipraz has proved to inhibit colitis-associated colon cancer. This research will form a basis for designing the first trial of a preventive treatment for people with this disease.
The drug’s ability to boost protective enzymes and decrease DNA damage from cancer-causing agents was thought to explain its success in halting the development and spread of a variety of tumors in mice and rats. But in evaluating this laboratory work, Clapper says, “we’ve seen tumor growth halted without an elevation of detoxification enzymes.”
That observation led the researchers to look at Oltipraz’ anti-angiogenesis ability. They started with studies using microarray technology, which can simultaneously analyze the activity of thousands of genes. This revealed that Oltipraz may have the ability to affect blood vessel growth.
A series of experiments in laboratory rodents then demonstrated that Oltipraz is an anti-angiogenic agent comparable in potency to two drugs currently being tested in clinical trials. One is SU 5416, now being tested at Fox Chase for patients with melanoma or sarcoma.
“Based on our work with animal tumor models, Oltipraz may not only be a cancer prevention agent but may also be effective in treating patients with advanced stage cancers and metastases,” Clapper explains. “We’re still doing pre-clinical testing,” she emphasized.
Cephalon is screening the drug in mice with several kinds of tumors to gain additional data about the most appropriate cancer sites for a future treatment trial of Oltipraz in humans. In addition to support from Cephalon and the Cancer Research Foundation of America, a National Institutes of Health grant and Commonwealth of Pennsylvania appropriation are helping fund research on Oltipraz’ anti-angiogenic activity.
Although still in clinical development for its broad-based chemoprevention activity, Oltipraz could turn out to be a doubly potent weapon against cancer—either helping prevent it in high-risk people or shrinking cancerous tumors by depriving them of their blood supply.
This wouldn’t be the first time Oltipraz showed promise beyond its established use, however. It was first approved as an anti-schistosomal treatment, to eliminate parasites known as blood flukes. In the same way, research aimed specifically at preventing cancer may serendipitously yield new approaches to cancer treatment as well.
Fox Chase Cancer Center, one of the nation’s first comprehensive cancer centers designated by the National Cancer Institute in 1974, conducts basic and clinical research; programs of prevention, detection and treatment of cancer; and community outreach. For more information about Fox Chase activities, visit the Center’s web site at http://www.fccc.edu or call 1-888-FOX CHASE.
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Clinical Cancer Research